Recent developments in chimeric NSAIDs as safer anti-inflammatory agents.

Recent Developments in Chimeric NSAIDs as Safer Anti-Inflammatory Agents Sharad Kumar Suthar and Manu Sharma Department of Pharmacy, Jaypee University of Information Technology, Waknaghat 173234, India Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/med.21331

䉲 Abstract: NSAIDs are among the most widely prescribed medications across the world, but the gastrointestinal (GI) toxicity still remains the biggest problem and the challenge for current NSAIDs-based therapeutics. The development of selective COX-2 inhibitors was driven by the assumption that selective inhibition of COX-2 would reduce the GI side effects. However, the initial enthusiasm for selective COX-2 inhibitors has faded away due to the emergence of serious side effects associated with the long-term use of these NSAIDs. In the recent years, a number of novel approaches to develop gastrosparing NSAIDs have been explored with the promising results. This review deals with such approaches and strategies that have been employed in the last two decades and are being used currently in the design and development C 2014 Wiley Periodicals, Inc. Med. Res. Rev., 00, No. 0, 1–67, 2014 of safer NSAIDs. Key words: NSAIDs; COX, inflammation; gastrointestinal toxicity

1. INTRODUCTION Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most widely prescribed medications around the world. Though, the long-term use of NSAIDs may cause gastrointestinal (GI) toxicity characterized by GI irritation, ulceration, dyspepsia, bleeding, abdominal pain, and diarrhea. NSAIDs have now overtaken Helicobacter pylori as the most common cause of GI injury in Western countries.1 It is believed that around 50% of patients administering NSAIDs on a chronic basis develop mucosal damage in the small intestine, and 2–4% of these individuals develop clinically significant GI ulcers and bleeding, occasionally leading to death.2 According to more than decade old studies, NSAIDs-associated GI complications account for over 100,000 hospitalizations and between 7000 and 10,000 deaths yearly in the United States.3–6 In a study published in 2005, the mortality rate among the patients with GI complications was over 5%.7 The anti-inflammatory activity of NSAIDs is associated with their ability to inhibit the activity of cyclooxygenase (COX) enzymes involved in the biosynthesis of prostaglandin H2 (PGH2 ). It is known that COX exists in two isoforms, namely COX-1 and COX-2, which are Correspondence to: Manu Sharma, Jaypee University of Information Technology, Waknaghat 173234, India. E-mail: [email protected] Medicinal Research Reviews, 00, No. 0, 1–67, 2014 C 2014 Wiley Periodicals, Inc.

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regulated differently. The COX-1 is constitutively expressed in the stomach, while elevated levels of COX-2 have been observed in the inflammatory cells.8 Long-term use of existing NSAIDs result in appreciable level of GI ulcers. Earlier it was thought that inhibition of COX-1 rather than that of COX-2 produces gastric ulcers.9–12 As a result, a number of selective COX-2 inhibitors, including celecoxib and rofecoxib were introduced for clinical use with exceptional anti-inflammatory properties and reduced gastric toxicity. However, the initial enthusiasm for selective COX-2 inhibitors seems to have all but evaporated due to the emergence of serious side effects associated with the chronic use of these NSAIDs and findings that COX-2-derived PGs were also critical for the protection of the GI tract against NSAID-induced injury. Clinical use of selective COX-2 inhibitors reduces the gastroduodenal damage but do not eliminate it.13, 14 Furthermore, COX-2 inhibitors are not able to eliminate NSAID-induced enteropathy15 and their use has also been associated with the cardiovascular adverse effects. Thus, the search for safer anti-inflammatory drugs still continue.16 The ability of various NSAIDs to produce gastroduodenal damage has been well correlated with their ability to inhibit mucosal PG synthesis.17, 18 Although majority of PGs in healthy stomach are derived from COX-1, but there are many evidences that COX-2-derived PGs also play a central role in the protection of gastroduodenal mucosa15, 19 and in the repair of mucosal damage throughout the GI system.20–22 The foremost PGs produced by human gastric mucosa are PGE2 and PGI2 with detectable levels of PGF2α and PGD2 have also been reported.23–26 PGs suppress gastric acid secretion via EP3 and IP receptors.26, 27 They stimulate mucus and bicarbonate secretion in the stomach, contributing to the resistance of epithelial cells to injury caused by pepsin and luminal acid and also promote repair of damaged epithelium.28, 29 In rodents these effects seem to be mediated via EP4 and EP1 receptors, correspondingly.30, 31 COX-1-derived PGs contribute enormously to the maintenance of a pH gradient at the mucosal surface.32 At the mucosal surface, PGs also increase the efficiency of the protective layer of surface-active phospholipids.33 In another function, PGs decrease the permeability of epithelial cells to suppress the acid-back diffusion.34 Maintenance of mucosal blood flow is important in case of damaged epithelium.15 PGs, namely E and I are potent vasodilators, increase mucosal blood flow to not only facilitate the repair of damaged tissues but also to boost the resistance of gastric mucosa against injury.35, 36 Moreover, increased blood flow assists in neutralization of back-diffusing acid and removes toxic substances that have entered the subepithelial space.15 COX-1-derived PGs maintains basal mucosal blood flow,37 while in cases where mucosal integrity is challenged, for example, ischemia-reperfusion injury, COX-2-derived PGs are of prime importance to maintain a blood flow.36 An acid-dependent decrease in blood flow has been observed following administration of COX-1-selective inhibitors.38 Inhibition of COX-1 also releases a potent vasoconstrictor substance endothelin-1.38 Furthermore, PGs inhibit the leukocyte adherence to the vascular endothelial cells, which contributes to the protective effects of PGs on the gastric mucosa.39 COX-2-derived PGD2 is an inhibitor of leukocyte recruitment during acute colitis,40 while its metabolites, including 15-deoxy12–14 PGJ2 plays a significant role in the resolution of inflammation in various tissues.41, 42 PGE2 is a potent inhibitor of inflammatory mediators, such as histamine, tumor necrosis factor-α (TNF-α), platelet-activating factor, interleukin-1 (IL-1), IL-8, and leukotriene B4 (LTB4 ).43–49 Accordingly, PGs help in ulcer healing by decreasing gastric acid secretion,33 increasing mucosal blood flow,50 mucus and bicarbonate secretions,51 and by stimulating the release of vascular endothelial growth factor (VEGF), which is responsible for the process of angiogenesis.52–54 Chronic treatment with NSAIDs disrupts the aforementioned activities of PGs leading to gastric toxicity/gastropathy and other adverse effects. An outline of beneficial functions of prostaglandins versus NSAIDinduced toxicity has been presented in Figure 1. Treatment with existing NSAIDs also produces bile, bacteria, and enterohepatic circulation-based NSAID enteropathy. To ameliorate before discussed adverse effects of clinically used NSAIDs, various approaches/strategies based on Medicinal Research Reviews DOI 10.1002/med

RECENT DEVELOPMENTS IN CHIMERIC NSAIDs

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the structural modification of NSAIDs have been reported. This review focuses on such approaches/strategies employed in the design and development of safer NSAIDs and their derivatives during the past and present times (Fig. 2.). Anti-inflammatory and analgesic activity data of NSAIDs and their derivatives developed in the recent past are summarized in Tables I-IV.

Figure 1.

Beneficial functions of prostaglandins versus NSAID-induced toxicity effects in GI system..TIF

Figure 2. Recent developments in chimeric NSAIDs as safer anti-inflammatory agents. GI, gastrointestinal; CVS, cardiovascular safety; VEGF, vascular endothelial growth factor; A. A. cascade, arachidonic acid cascade.

Medicinal Research Reviews DOI 10.1002/med

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Table I. In Vitro COX Inhibitory Activity of NSAID Derivatives Compd. 14 21 22 25 38 39 40 41 42 43 46 47 48 50 53 54 55 97 98 99 100 101 105 106 107a 107b 108 109 110 111 112 113 114 115 116 117 119 120 121 122 124 125 126 127 128 129 129 130

COX-1, IC50 μM (reference IC50 , μM)


0.60 (keto: 0.33) 67% at 100 μM (tolfen: 69%) 61% at 100 μM (tolfen: 69%) 34.7 (cele: 7.7) >100 (asp: 0.3) >100 (asp: 0.3) >100 (ibu: 2.9) >100 (ibu: 2.9) >100 (indo: 0.1) >100 (indo: 0.1) >100 (indo: 0.1) >100 (indo: 0.1) 5.8 (cele: 115.9) 0.03 (asp: 0.30) 77.7 (npr: 0.18) 1.1 (ibu: 4.0) 14.6 (ibu: 4.0) 66.00 (indo: 0.050) 27.00 >100 0.00% at 10 μM 2.60 (indo: 0.05) 0.147 (sulin: 0.115) 18.00 (cele: 1.88) 0.043 (R-keto: 0.695) 0.083 (S-keto: 0.003) 65.55 (cele:24.3) >100 (cele:24.3) 25.00 (NS-398: 37) 326.0 (cele: 7.0) 15.6 (loxo: 23.5) 0.06 (mef acid: 0.04) 66.0 (mef acid: 0.04) 1.03 (cele: 2.60) – 59.7 (cele: 10.7) >100 (rofe: >500) >100 (rofe: >100) 0.0038 (cele: 0.0037) 140.0 0.05 (valde: 27) 0.115 (rofe: >1000) 2.78 (imre: 0.115) 0.087 (imre: 0.115) 116 – – 0.570 (DMSS: 1.8)

0.73 (keto: 0.69) 85% at 100 μM (tolfen: 64%) 56% at 100 μM (tolfen: 64%) 12.8 (cele: 0.12) >100 (asp: 2.4) >100 (asp: 2.4) >100 (ibu: 1.1) >100 (ibu: 1.1) >100 (indo: 5.7) >100 (indo: 5.7) 0.6 (indo: 0.1) 9.3 (indo: 0.1) 6.1 (cele: 0.065) 0.38 (asp: 2.40) 0.42 (npr: 12.4) 15.8 (ibu: 1.4) 0.63 (ibu: 1.4) 0.040 (indo: 0.75) 0.0003 0.04 93% at 10 μM (cele: 100%) 4.20 (indo: 0.75) 0.375 (sulin: 0.140) 0.20 (cele: 0.11) 71.00 (R-keto: 80.00) 55.00 (S-keto: 05.00) 0.057 (cele: 0.06) 0.077 (cele: 0.06) 0.32 (NS-398: 0.09) 11.0 (cele: 0.19) 21.3 (loxo: 10.1) 0.05 (meclo: 0.05) 0.15 (meclo: 0.05) 0.13 (cele: 0.35) 20.7 (indo: 0.40) 0.235 (cele: 0.036) 0.00126 (rofe: 0.0567) 0.9 (rofe: 0.5) 0.0018 (cele: 0.0022) 0.005 1.49 (valde: 0.57) 0.018 (rofe: 0.0047) 0.41 (imre: 0.018) 0.014 (imre: 0.018) 1.1 0.0096 (lumi: 0.0033)a 8.9 (lumi: 0.138)b 1% at 4 μM


Reference 62 78 78 81 89 89 89 89 89 89 91 91 92 93 100 100 100 180 181 182 183 184 186 188 189 189 190 190 191 193 194 195 195 196 197 198 201 202 203 204 213 214 215 215 216 217 217 218


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Table I. Continued Compd. 131 132 133 135 136 137 138 139 140 150



0.470 (DMSS: 1.8) 0.09 0.5 >100 (ibu: 2.90) 13.2 (cele: 7.7) 10.2 (cele: 7.7) 13.1 (cele: 7.7) >100 (rofe: >100) >100 (rofe: >100) >200 (indo: 0.01)

15% at 4 μM 2.49 >100 2.60 (ibu: 1.10) 7.5 (cele: 0.07) 7.5 (cele: 0.07) 0.69 (cele: 0.12) 1.4 (rofe: 0.5) 2.7 (rofe: 0.5) 49 (indo: 18)

Reference 218 219 219 226 227 227 228 229 229 264

Unless and otherwise stated activity presented are in IC50s (␮M). The activity of compounds 21, 22, 100, 130 (COX-2 inhibition), and 131 (COX-2 inhibition) are presented as percentage of inhibition of COX enzymes. a Activity in isolated monocytes. b Actvity in human whole blood.

Table II. Activity of NSAID Derivatives against LOXs Compd.

LOX

IC50 μM (reference IC50, μM)

22 134 134 135 136 137 138 139 139 140 140 142

LOX 5-LOX (5-LO broken cell assay) 5-LOX (5-LO human whole blood assay) 5-LOX 5-LOX 5-LOX 5-LOX 5-LOX 15-LOX 5-LOX 15-LOX 5-LOX

35 (NDGA: 1.3) 0.2 (zileuton: 0.5) 1.0 (zileuton 0.76) 0.28 (caffeic acid: 4) 0.39 (caffeic acid: 3.47) 4.90 (caffeic acid: 3.47) 5 (caffeic acid: 4) 0.28 (caffeic acid: 3) 0.32 (NDGA: 3.5) 0.30 (caffeic acid: 3) >10 (NDGA: 3.5) 0.9 (BWA4C: 0.16)

Reference 78 225 225 226 227 227 228 229 229 229 229 230

2. DEVELOPMENT OF VARIOUS NSAIDs AND THEIR DERIVATIVES A. NO-, HNO-, and H2 S-Releasing (Gaseous Mediator Releasing) NSAIDs Both NO and H2 S inhibit adhesion of leukocytes to the vascular endothelium and act as vasodilators. These gaseous mediators enhance the resistance of the gastric mucosa against injury, repair the mucosal damage, and facilitate the resolution of inflammation. Therefore, it is supposed that NO- and H2 S-releasing NSAIDs may conquer the limitations associated with the existing NSAIDs. Thus, numerous researchers around the world have made efforts to exploit the aforementioned properties of NO and H2 S in the development of novel NO-, HNO-, and H2 S-releasing NSAIDs. Schematic outline of NO–NSAIDs is depicted in Figure 3, while NO–, HNO– and H2 S–NSAID derivatives (1–63) developed in the recent past have been summarized in Figures 4–6. Medicinal Research Reviews DOI 10.1002/med

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Table III. In Vivo Anti-Inflammatory Activity of NSAID Derivatives

Compd.

Percentage edema inhibition/ED50 /ID50 (reference% edema inhibition ED50 /ID50 )

Percentage edema progression (reference% edema progression)

Reference

10 11 19 21 22 23 24 25 35 36 38 39 40 41 42 43 44 44 46 47 48 50 51 52 53 54 55 62 63 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 80 84

54.9% (asp: 57.4%) 51.5% (asp: 57.4%) 49% (npr: 52%) 46.16% (tolfen: 28.97%) 42.43% (tolfen: 28.97%) 54.0% (diclo: 55.0%) 48% (asp: 42%) ED50 : 118.4 mg/kg (cele: 10.8 mg/kg) – 63.3% (ibu: 48.5%) ID50 : 181.8 mg/kg (asp: 128.7 mg/kg) ID50 : 151.2 mg/kg (asp: 128.7 mg/kg) ID50 : 66.8 mg/kg (ibu: 67.4 mg/kg) ID50 : 62.3 mg/kg (ibu: 67.4 mg/kg) ID50 : 10.7 mg/kg (indo: 4.2 mg/kg) ID50 : 5.9 mg/kg (indo: 4.2 mg/kg) ED50 : 314 μM/kg (asp: 710 μM/kg) ED50 : 18.5 μM/kg (indo: 11.8 μM/kg) 42.2% (indo: 50.0%) 53.6 (indo: 50.0%) ED50 : 168.1 μM/kg (cele: 30.9 μM/kg) 58% (asp: 50%) ID50 : 169 mg/kg (asp: 129 mg/kg) ID50 : 121 mg/kg (asp: 129 mg/kg) ID50 : 19.1 mg/kg (npr: 29.7 mg/kg) 79.5% 78.9% – – ED50 : 3.2 mg/kg (indo: 4.2 mg/kg) – – – – 66.84% (ibu: 47.62%) – 87% (asp: 88%) 86% (asp: 88%) 96% (asp: 88%) 85% (4-BPA: 61%) 89% (flur: 85%) 46.74% (indo: 45.43%) 88.60% (keto: 86.80%) 87% 90% (CEES) (diclo: 17%) 24% (TPA) (diclo: 58%) –

– – – – – – – – 54.90% (asp: 43.00%) – – – – – – – – – – – – – – – – – – 0.15 mL (npr: 0.25 mL) 0.21 mL (sulin: 0.22 mL) – 16.83% (diclo: 20.50%) 34.20% (4-BPA: 26.90%) 40.46% (indo: 57.39%) 38.22% (indo: 57.39%) – 25.39% (indo: 37.93%) – – – – – – – – – – 13.07% (diclo: 12.87%)

58 58 76 78 78 79 80 81 86 87 89 89 89 89 89 89 90 90 91 91 92 93 99 99 100 100 100 111 111 113 119 120 121 121 122 123 138 138 138 144 144 145 146 147 155 155 170



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Table III. Continued

Compd.

Percentage edema inhibition/ED50 /ID50 (reference% edema inhibition ED50 /ID50 )

Percentage edema progression (reference% edema progression)

86 87 92 93 94 95 100 102 103 104 112 115 118 121 122 123 125 126 127 135 136 137 138 139 140 144 148 149 152 153 154 155 156 157 158 159 161 162 163 164 165 166 167 170

– 57.72% (ketorol: 64.24%) 52.67% (ibu: 45.90%) 51.56% (flur: 53.00%) 70% (mef acid: 40%) 63.3% (indo: 41.6%) 88% (cele: 49%) 35% (cele: 35%) 27% (cele: 35% 48% (cele: 35%) 60.1% (loxo: 53.1%) 62.84% (nime: 44.32%) 41.0% (cele: 24.2%) 34.1% (parecox: 62.8%) ED50 : 10.2 mg/kg ED50 : 5.0 mg/kg 17.3% (rofe: 21.7%) 63.9% (imre: 50.4%) 65.9% (imre: 49.3%) ED50 : 258 μM/kg (asp: 716 μM/kg) ED50 : 66.9 mg/kg (cele: 10.8 mg/kg) ED50 : 99.8 mg/kg (cele: 10.8 mg/kg) ED50 : 27.7mg/kg (cele: 10.8 mg/kg) 33.7% (cele: 79.9%) 25.5% (cele: 79.9%) – 80.07% (diclo: 71.30%) 48.39% (indo: 48.39%) 53.29% (ibu: 52.38%) 48.03% (ibu: 52.15%) 53.48% (ibu: 52.15%) 90% (ibu: 42%) 73% (ibu: 42%) 87.90% (ibu: 76.10%) 81.05% (npr: 81.81%) – – 71.29% (6-MNA: 52.51%) 43.89% (diclo: 41.92%) 38.1% (ibu: 62.5%) 50.0% (npr: 46.9%) 69.28% (indo: 63.83%) 68.0% (keto: 56.2%) –

17.15% – – – – – – – – – – – – – – – – – – – – – – – – 31.18% (salicyl: 28.95%) – – – – – – – – – 0.26 mm (npr: 0.17 mm) 4.79 mm (asp: 4.82 mm) – – – – – – 4.80 mm (diclo: 5.55 mm)

Reference 171 172 175 176 177 178 183 185 185 185 194 196 199 203 204 205 214 215 215 226 227 227 228 229 229 258 262 263 266 267 267 268 268 269 270 271 274 279 281 282 282 283 284 287

Unless specified, results presented are as percentage edema inhibition or as percentage edema progress.


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Table IV. In Vivo Analgesic Activity of NSAID Derivatives Determined in Different Assays Compd.

Analgesic activity (activity of reference compd.)

28 29 30 31 32 44 45 66 67 68 69 71 77 84 85 91 94 103 139 140 144 148 151 152 153 154 155 156 159 166 167

32% w.i. (diclo: 84%) 95% w.i. (diclo: 84%) 58% w.i. (diclo: 84%) 70% w.i. (diclo: 84%) 53% w.i. (diclo: 84%) 65.8% w.i. (asp: 64.3%) 61.5% w.i. (indo: 67.6%) 71.39% w.i. (diclo: 70.90%) 62.40% w.i. (4-BPA: 68.60%) 86.70% w.i. (indo: 74.17%) 89.43% w.i. (indo: 74.17%) 25.39% w.i. (indo: 37.93%) 39.89% w.i. (indo: 42.08%) 120 V (diclo:150.2 V) 163 V (diclo: 150.2 V) 74.29% w.i. (ibu: 74.29%) 61% w.i. (mef acid: 74%) 59% w.i. (sulin: 49%) 49.0% w.i. (cele: 62.0%) 52.2% w.i. (cele: 62.0%) 169 V (salicylamide: 139 V) 68.66% w.i. (diclo: 64.65%) 98% w.i. (ibu: 80%) 50.02% w.i. (ibu: 52.85%) 29.63% analgesia (ibu: 23.42%) 35.84% analgesia (ibu: 23.42%) 76.49% increase in r.t. (diclo: 79.24%) 79.60% increase in r.t. (diclo: 79.24%) 40.83% w.i. (npr: 78.01%) 83.21% w.i. (indo: 78.55%) 94.10% analgesia (keto: 88.7%)

Reference 84 84 84 84 84 90 90 119 120 121 121 123 145 170 170 175 177 185 229 229 258 262 265 266 267 267 268 268 271 283 284

w.i., writhing inhibition; r.t., reaction time.

1. Nitrate and Dinitrate Esters Lechi and fellow workers investigated the antiplatelet activity of NO-releasing aspirin derivative 2-acetoxybenzoate 2-(1-nitroxymethyl)phenyl ester (NCX-4016) (1).55 The authors observed that NCX-4016 almost completely inhibited platelet thromboxane A2 (TXA2 ) production and arachidonic acid induced platelet aggregation. The antiplatelet activity of NCX-4016 was attributed to the NO-release and COX inhibition. Likewise, Lazzarato et al. synthesized a new class of NO-releasing aspirin-like molecules in which phenol group of salicylic acid was linked to the alkanoyl moieties bearing nitrooxy functions.56 All the screened products displayed in vivo anti-inflammatory potency similar to that of aspirin and unlike aspirin showed less ulcerogenicity. The highly potent derivatives that produced anti-inflammatory effects equipotent to aspirin belonged to the classes of both mononitrooxy (compounds 2–4) and dinitrooxy derivatives (compounds 5–7) and the compound 6 with dinitrooxy substitution and ethylene spacer displayed maximum edema inhibition. Persisting with their efforts to discover potent and safer NSAIDs, Lazzarato and associates further prepared a novel NO-donating series of (nitrooxyacyloxy)methyl esters of aspirin.57 In this new array of compounds, release of aspirin Medicinal Research Reviews DOI 10.1002/med


Figure 3.

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Schematic representation of NO–NSAIDs.

varied with the nature of nitrooxyacyloxy moiety present in the molecules and the compounds of aromatic series were more active than the aliphatic ones. The antiaggregatory activity of the products was performed on a collagen-induced platelet aggregation of human platelet-rich plasma (PRP) using aspirin as the reference compound, while the vasodilatory effect of newly synthesized products was studied on endothelium-denuded rat aorta strips precontracted with phenylephrine. The compound 8 was found to be the most potent antiaggregatory agent with IC50 of 20 μM, whereas 9 exhibited highest vasodilatory effects with EC50 of 0.017 μM. In an effort to improve the bioavailability, Rolando et al. synthesized a novel series of water-soluble (benzoyloxy)methyl esters of aspirin.58 All the synthesized derivatives possessed alkyl chains containing a NO-releasing nitrooxy group and a solubility-enhancing aminoacyloxy moiety attached to the benzoyl ring. Results of anti-inflammatory screening using a carrageenan-induced paw edema assay in rats indicated that aspirin prodrugs, {[2(acetyloxy)benzoyl]oxy}methyl-3-[(3-[aminopropanoyl)oxy]-4-[3-(nitrooxy)propoxy]benzoate hydrochloride (10) and {[2-(acetyloxy)benzoyl]oxy}methyl-3-(morpholin-4-ylmethyl)-4-[3(nitrooxy)propoxy]benzoate oxalate (11) showed anti-inflammatory effects similar to those of aspirin. The gastrotoxicity of the two prodrugs was also found to be lower than that of aspirin in a lesion model in rats. As a result, these NO-releasing aspirin prodrugs merit further investigation for therapeutic applications. Diclofenac has been used as a potent NSAID for decades and chemically belongs to the class of acetic acid derivatives. Viappiani et al. documented the anti-inflammatory, analgesic, and GI tolerability profile of diclofenac derivative NCX-285, a COX-inhibiting nitric oxide donator (CINOD).59 NCX-285 displayed dose-dependent inhibition of carrageenan-induced paw edema, with highest dose (47 mg/kg) reducing paw volume by 63%. NCX-285 also decreased the pain score in arthritic rats from 2.7 to 0.7 at 4.3 mg/kg dose. In both assays, antiinflammatory and analgesic effects of NCX-285 were similar to those of reference diclofenac. The doses of NCX-285 producing 50% of gastric and intestinal damage were, respectively, sevenfold (21.4 vs. 3 mg/kg) and twofold greater (12.8 vs. 6.3 mg/kg) than diclofenac, demonstrating reduced GI toxicity of NCX-285. In brief, NCX-285 displayed anti-inflammatory and analgesic activities equipotent to diclofenac with a noticeably reduced GI damage, thus, providing a valuable therapeutic option for the treatment of osteoarthritis. Indomethacin is another acetic acid derivative, chemically known as 2-(1-[(4-chlorophenyl)carbonyl]-5-methoxy-2methyl-1H-indol-3-yl)acetic acid. Mizoguchi and co-workers studied the anti-inflammatory and Medicinal Research Reviews DOI 10.1002/med

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Figure 4.

NO- and H2 S-releasing NSAID derivatives (1–23).



Figure 5.

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NO- and H2 S-releasing NSAID derivatives (24–45).


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Figure 6.

NO-, HNO-, and H2 S-releasing NSAID derivatives (46–63).



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ulcerogenic properties of NO-releasing indomethacin (NCX-530) (12). It was found that unlike indomethacin, the NO-releasing indomethacin derivative NCX-530 does not cause gastrotoxicity, despite inhibiting COX activity and exhibiting anti-inflammatory effects.60 The decreased gastric toxicity of NCX-530 was accounted to the inhibition of enterobacterial translocation, perhaps caused by NO-mediated increased mucus and fluid secretions. The authors further observed that the NCX-530 had a potent anti-inflammatory action, as effective as the indomethacin, in the carrageenan-induced rat paw edema assay. Ketoprofen is structurally 2-(3-benzoylphenyl)propanoic acid. Gaitan et al. reported a potent antinociceptive agent HCT-2037 (13), a NO-releasing derivative of S-ketoprofen.61 Results indicated that HCT-2037 was twofold more potent than ketoprofen (ID50 : 0.75 μM/kg vs. S-ketoprofen 1.3 μM/kg) in response to noxious mechanical stimuli, while in the animals with carrageenan-induced inflammation, it almost completely suppressed mechanical allodynia (91% reduction vs. S-ketoprofen 50%) and hyperalgesia (94% reduction vs. S-ketoprofen 40%). Thus, the finding of a highly efficacious and safe NSAID HCT-2037 has opened a new window for the development of potent antinociceptive agents. In another study of NO-releasing profen analogs, Bézière et al. designed and synthesized NO–profen hybrid molecules.62 Among them, a NO–ketoprofen hybrid compound (14) exhibited COX-2 inhibition comparable to that of ketoprofen. Flurbiprofen is an analog of ketoprofen. In search of potentially safer NSAIDs, Wallace et al. investigated the anti-inflammatory and ulcerogenic properties of the nitroxybutyl derivative of flurbiprofen named HCT-1026 (15).63 This new derivative displayed markedly less gastric toxicity and suppressed prostaglandin synthesis comparable to that of flurbiprofen. It also inhibited collagen-induced platelet aggregation significantly higher than the native NSAID. Accordingly, HCT-1026 represents a novel class of NSAIDs with appreciably less ulcerogenic effects on the stomach. Naproxen is a member of 2-arylpropionic acid/profen class of NSAIDs. With the objective to augment the COX inhibitory potential, Kartasasmita et al. synthesized NO-releasing N- and S-nitrooxypivaloyl-cysteine naproxen derivatives.64 Though, when screened for COX-1 inhibition in a human platelet cell assay and for COX-2 inhibition in mononuclear cells from whole blood, N-nitrooxyacylcysteine derivative (N-3-nitrooxypivaoyl-S-(+)-2-(6-methoxy-2naphthyl)-propanoyl-L-cysteine ethyl ester) appeared inactive, while the S-nitrooxyacylcysteine derivative (N-(+)-2-(6-methoxy-2-naphthyl)propanoyl-S-3-nitrooxypivaloyl-L-cysteine ethyl ester (16) possessed only feeble potency against COX-1. The highly promising NO–naproxen hybrid, naproxcinod (17) is a CINOD65 that has been investigated in phase III clinical studies. Naproxcinod has been found to be as effective as the naproxen while showing GI tolerability superior to the naproxen. In Freund’s adjuvant arthritic rats at 15 mg/kg dose, it significantly decreased hindpaw swelling. It also reduced plasma level of IL-6, a marker of systemic inflammation in rheumatoid arthritis. In Freund’s complete adjuvant (FCA) injected rats, naproxen (10 mg/kg) exhibited gastric mucosal injury score of 22.1 ± 4.6 mm, while naproxcinod (15 mg/kg, equivalent to dose of naproxen) caused significantly less injury with gastric mucosal injury score of 6.8 ± 0.9 mm only (P < 0.05 vs. naproxen). Expression of gastric COX-1, mRNA, and protein did not differ among normal rats, FCA-injected rats, and naproxen and naproxcinod-treated groups of Freund’s adjuvant arthritic rats. However, enhanced levels of COX-2, mRNA, and protein were seen in the naproxen-treated group, whereas no significant induction of COX-2 was observed in rats treated with naproxcinod. Moreover, naproxcinod inhibited gastric PGE2 generation in arthritic rats to the same extent of naproxen.66 In a proof of concept study in humans, 31 subjects were randomized to receive placebo, naproxen 500 mg twice daily, or naproxcinod in an equimolar dose of 750 mg twice daily for 12 days in a double-blind three-period crossover volunteer study. In a naproxcinod-treated group, the mean total number of gastroduodenal erosions was found to be 4.1 with more than half Medicinal Research Reviews DOI 10.1002/med

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of the subjects free from erosions. On the contrary, the mean total number of gastroduodenal erosions was found to be 11.5 with one subject developing an acute ulcer in the naproxentreated group. Furthermore, naproxcinod and placebo treatment did not increase intestinal permeability in subjects, whereas naproxen treatment did increase it.67 In one of the phase II studies (970 patients randomized (7:7:2) to naproxcinod 750 mg twice daily, naproxen 500 mg twice daily, or placebo twice daily in a double-blind study), naproxcinod-treated subjects demonstrated a 30% lower incidence of endoscopic gastroduodenal ulcers compared with the naproxen-treated subjects, but this study failed to achieve statistical significance (P = 0.07).68 In a 6-week study of 543 patients with osteoarthritis of hip or knee (subjects were randomized to receive naproxcinod 750 mg once daily, 750 mg twice daily, 1125 mg twice daily or placebo), all the subject groups showed statistically significant reductions in WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) pain score compared with the placebo (P 0.02). Naproxcinod was well tolerated among the subjects and 750 mg twice a day dose was found to be the best balance of benefit versus safety.69 In a phase III randomized clinical trial of 916 patients with osteoarthritis, after 13 weeks of therapy, naproxcinod 750 mg twice daily reduced systolic blood pressure compared to naproxen 500 mg twice daily (P < 0.02). Naproxcinod 750 or 350 mg twice a day also displayed reductions from baseline in diastolic blood pressure compared to naproxen 500 mg twice a day (P < 0.04).70 Further phase III clinical trials include efficacy and safety study of naproxcinod in subjects with osteoarthritis of hip71 and knee.72, 73 In a recent study of naproxcinod effects on the skeletal and cardiac disease phenotype in mdx mice (a strain of mice with hereditary disease of the muscles), naproxcinod at 21 mg/kg/day for 9 months resulted in significant improvement in hindlimb grip strength and a 30% decrease in inflammation in the fore and hindlimbs. A significant improvement in heart function was evidenced by improved fraction shortening, ejection fraction, and systolic blood pressure. These results indicated that naproxcinod can be potent and safe therapeutic option to treat muscular dystrophies.74 Current status of naproxcinod has been discussed in the later part of the manuscript. Another gastroprotective NO-donating naproxen hybrid NMI-1182 (2,3bis(nitrooxy)propyl 2-(6-methoxynaphthalen-2-yl)propanoate) (18) was developed by Ellis et al.75 NMI-1182 produced COX inhibition activity similar to the naproxen and developed appreciably less gastric lesions after oral administration than naproxen. NMI-1182 also significantly inhibited carrageenan-induced paw edema in the rat, while in the carrageenan air pouch model, it markedly reduced PGE2 level (90%, while naproxen-Na 93%) along with the inhibition of leukocyte influx. The results indicated that NMI-1182 possessed anti-inflammatory activity comparable to that of naproxen, but with a less likeliness to cause intestinal damage. In a different study, a new series of NO-releasing naproxen analogs were developed by Ranatunge and co-workers. They described the synthesis and biological evaluation of NO-releasing prodrugs of N-substituted naproxen glycolamides.76 Among them, prodrug N-methyl-N-(((3-(nitrooxy)propyl) oxycarbonyl)methyl)carbamoyl)methyl(2S)-2-(6methoxy(2-naphthyl) propanoate (19) displayed the paramount anti-inflammatory activity. Continuing their efforts in search of potentially safer NSAIDs, J. L. Wallace group further reported GI sparing effects of NO-releasing naproxen derivative NCX-429 ((S)-6-(nitrooxy)hexyl 2-(6-methoxynaphthalen-2-yl)propanoate) (20).77 NCX-429 was evaluated in healthy, arthritic, aged rats (19 months), and rats coadministered low-dose aspirin and/or omeprazole. At doses displaying equipotent anti-inflammatory activity to the naproxen and celecoxib, NCX-429 showed significantly less GI damage than naproxen. When coadministered with low-dose aspirin or omeprazole, it demonstrated negligible small intestine damage in contrast to the injury caused by naproxen and celecoxib. Tolfenamic acid is a fenamic acid derivative indicated for use in migraine. Intending to improve anti-inflammatory activity and GI tolerability of tolfenamic acid, Ziakas and co-workers Medicinal Research Reviews DOI 10.1002/med


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developed NO-releasing analogs of tolfenamic acid.78 Among them, 3-nitrooxypropyl 2-(3chloro-2-methylphenyl amino)benzoate (21) exhibited highest activity against COX-2, while compound 2-nitrooxy-1-nitrooxymethylethyl 2-(3-chloro-2-methylphenylamino)benzoate (22) was found to be a better inhibitor of LOX. At 4 days treatment with equimolar doses, tolfenamic acid showed 100% incidence of perforating ulcers, while 21 caused no perforating ulcers. The structure–activity relationship (SAR) study revealed that chain of two to three carbon atoms between carboxylic and nitric ester functions was the most favorable for the inhibition of both COX and LOX activity. Nemmani and fellow workers synthesized novel NO-releasing hybrids of aspirin and diclofenac.79 Among these compounds, NO–diclofenac (23) emerged as the lead compound with the most promising pharmacokinetic, anti-inflammatory, and NO-releasing properties and protected rats from NSAID-induced gastric damage. In the in vivo anti-inflammatory assay, 23 showed edema inhibition equal to that of parent compound diclofenac. In an effort to discover novel NO-releasing NSAIDs as potentially safe anti-inflammatory agents, Borhade et al. designed, synthesized, and evaluated 21 new NO–NSAIDs of conventional anti-inflammatory drugs, viz. aspirin, diclofenac, naproxen, flurbiprofen, ketoprofen, sulindac, ibuprofen, and indomethacin.80 These conjugates possessed NO-donating disulfide linker attached to the parent NSAID through linkages, such as an ester, a double ester, an imide, or an amide. Among them, the ester-bearing NO–aspirin, NO–diclofenac, and NO–naproxen, and the imide-bearing NO–aspirin, NO–flurbiprofen, and NO–ketoprofen showed significant oral absorption, anti-inflammatory effects, and a NO-donating property, and also protected rats from NSAID-triggered GI toxicity. NO–aspirin conjugate (24) with imide linkage was further coevaluated with aspirin at equimolar doses and displayed comparable dose-dependent pharmacokinetics, suppression of gastric mucosal PGE2 synthesis, and analgesic properties to those of aspirin but retained its gastrosparing characters. The efficacy and safety of these potential conjugates indicate that they hold a great promise for further development as anti-inflammatory agents. Experimenting with the current trend, Chowdhury and fellow workers synthesized NOreleasing celecoxib analogs bearing N-(4-nitrooxybutyl)piperidin-4-yl or N-(4-nitrooxybutyl)1,2,3,6-tetrahydropyridin-4-yl moiety.81 These compounds were moderately selective toward COX-2 with analog 25 exhibiting COX-2 selectivity index of 2.7. In the in vivo antiinflammatory assay, compounds bearing MeSO2 pharmacophore were found to be more active than the compounds possessing SO2 NH2 pharmacophore. The compound 25 that possessed MeSO2 pharmacophore and N-(4-nitrooxybutyl)-1,2,3,6-tetrahydropyridyl moiety exhibited significant in vivo anti-inflammatory activity. In order to overcome the GI toxicity, Engelhardt et al. designed and synthesized a new class of NO-releasing prodrugs of rofecoxib.82 In the in vivo studies, prodrug 26 proved to be beneficial with significantly reduced GI toxicity. Intending to discover gastro and cardioprotective NSAID, Schroeder et al. designed and synthesized a NO-donating and COX-2-selective valdecoxib derivative NMI-1093 (27).83 The study disclosed that NMI-1093 had COX-2 selectivity and potency comparable to those of standard COX-2-selective inhibitors and this comparison was extended in vivo to NMI-1093’s efficacy as an anti-inflammatory drug in the rat air pouch and carrageenan-induced paw edema assays of inflammation. The investigators believed gastro and cardioprotective profile of NMI-1093 would be due to NO donation by NMI-1093. However, in this report, they did not describe it in detail. 2. Nitrosothiols (R-SNO) S-nitrosothiols or thionitrites are compounds with general structure of R-SNO, where nitroso group is attached to the sulfur atom of thiol. In these compounds, nitrosothiol (-S-NO) moiety Medicinal Research Reviews DOI 10.1002/med

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acts as the NO donator. Aiming to improve the pharmacological and metabolic profile of diclofenac, Bandarage and associates synthesized nitrosothiol esters of diclofenac.84 The S-NO– diclofenac derivatives 28–32 exhibited anti-inflammatory and analgesic activities comparable to those of diclofenac. All the screened ester derivatives produced negligible stomach lesions compared with the parent compound. The compound 29 was found to be the most potent analgesic agent that displayed highest inhibition of writhing. On the other hand, compounds 31–32 emerged as the most potent anti-inflammatory agents. Increasing the alkyl spacer chain length from ethylene (31) to propylene (32) increased the anti-inflammatory potency, though, a further increase in spacer chain length (33) resulted in decreased activity. 3. Furoxans and Benzofuroxans Furoxan or 1,2,5-oxadiazole 2-oxide is an amine oxide derivative of furazan, which serves as the NO donator. Cena and colleagues prepared NO-releasing prodrugs of aspirin in which aspirin was bonded to the substituted furoxan moiety via an ester linkage.85 All the synthesized prodrugs were screened for anti-inflammatory, antiaggregatory, and ulcerogenic properties. Among them, prodrug 34 with cyano-substituted furoxan moiety exhibited maximum antiinflammatory and antiaggregatory potential with reduced GI toxicity. Continuing with their research on NO-releasing NSAIDs, Lazzarato and associates further developed salicylic acid analogs containing NO-donating furoxans and des-NO-furazans as anti-inflammatory agents.86 The phenylsulfonyl- and cyano-substituted furoxans inhibited platelet aggregation via cGMPdependent mechanism. In vivo anti-inflammatory activity of all the synthesized molecules was similar to that of aspirin and among them compound 35 was found to be the most potent inhibitor of inflammation that also showed decreased GI toxicity. The ibuprofen or 2-(4-isobutylphenyl)propanoic acid is a nonselective COX inhibitor. The new generation NO-releasing ibuprofen–furoxan conjugates were developed in the lab of M. L. Lolli and evaluated for anti-inflammatory, antiaggregatory, and ulcerogenic effects.87 All the synthesized conjugates showed anti-inflammatory activity comparable to that of ibuprofen with GI toxicity less than ibuprofen. Compound 36 that possessed benzenesulfonyl substitution on the furoxan moiety was found to be the most potent anti-inflammatory and antiaggregatory agent. Analogs that were able to release NO demonstrated antiaggregatory effects superior to the parent ibuprofen. In another NO-donating NSAIDs-based approach, Carvalho and fellow workers reported the synthesis of NO-releasing diclofenac derivative bearing a benzofuroxan moiety.88 The compound, 1-oxy-benzo[1,2,5]oxadiazol-5-ylmethyl[2-(2,6-dichlorophenyl amino)-phenyl] acetate (37) was synthesized by a reaction between diclofenac sodium and 5-bromomethyl-benzo[1,2,5] oxadiazole 1-oxide. In the in vivo anti-inflammatory assay, 37 showed potency similar to that of diclofenac. The ulcerogenic potential of compound 37 was also found to be lower than that of diclofenac. 4. Diazeniumdiolates (NONOates) Diazen-1-ium-1,2-diolates are compounds with general structural unit of X-[N(O)NO]− , where X is a nucleophile residue. Diazeniumdiolate ions transport NO to the specific tissues and without metabolic activation they can release up to two equivalents of NO. These characteristics distinguish NONO–NSAIDs from currently available nitrate-based NO–NSAIDs that needed redox activation for NO release. Recent studies have discovered that certain diazeniumdiolates can also generate HNO along with the generation of NO on hydrolysis. Velázquez et al. synthesized NO-releasing ester conjugates of classical NSAIDs (aspirin, ibuprofen, and indomethacin) attached to the 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate or 1-(N,N-dimethylamino)diazen-1ium-1,2-diolate moiety via a one-carbon methylene spacer.89 When evaluated, conjugates 38–43 displayed in vivo anti-inflammatory activity equipotent to parent NSAIDs. In vivo ulcer index Medicinal Research Reviews DOI 10.1002/med


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(UI) study showed that the aspirin conjugates 38 and 39 and the ibuprofen conjugates 40 and 41 induced no lesions at all. On the contrary, at equipotent doses, UIs of parent drugs aspirin and ibuprofen were found to be 57 and 45, respectively. Compounds possessing a 1-(pyrrolidin1-yl)diazen-1-ium-1,2-diolate moiety (38, 40, and 42) were less potent than the compounds possessing a 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate moiety (39, 41, and 43). Aspiring to develop the next-generation NO-releasing NSAIDs, Velázquez and co-workers further synthesized NSAID derivatives in which carboxylic function of aspirin and indomethacin was covalently bonded to the 1-(2-carboxypyrrolidin-1-yl)diazen-1-ium-1,2-diolate ion through a one-carbon methylene spacer.90 Among the compounds screened for in vivo anti-inflammatory activity, aspirin derivative 44 was 2.2 times more potent than aspirin, while indomethacin derivative 45 was 1.6 times less potent than indomethacin. Dissimilarity between the activity ratio of 44 and 45 was caused by their differences in absorption, distribution, and metabolism parameters. Both derivatives 44 and 45 were proved to be less ulcerogenic than their parent drugs aspirin and indomethacin, respectively. Contemporary to the previous study, Abdellatif et al. developed dinitroglyceryl and diazen1-ium-1,2-diolated NO-releasing ester conjugates of aspirin, indomethacin, and ibuprofen, wherein NO-releasing moiety was directly attached to the carboxyl group of the NSAIDs.91 Indomethacin ester (46) appeared as the exceedingly potent agent against the COX-2 activity with potency superior than aspirin, indomethacin, and ibuprofen. In the in vivo anti-inflammatory assay, indomethacin congeners 46 and 47 exhibited significant inhibition of edema as well. Sticking with the synthesis of NO-donating NSAIDs-based approach to improve pharmacological activity and selectivity, Abdellatif and co-workers further reported the development of NO-releasing conjugates of celecoxib bearing a diazen-1-ium-1,2-diolate moiety.92 All the synthesized compounds showed feeble activity against COX-1, while against COX-2 they exhibited weak to moderately weak activity. In the in vitro COX inhibition assay, compound 48 showed maximum potency, while in the in vivo anti-inflammatory assay it showed four- and twofold superior activity than aspirin and ibuprofen, respectively. Recently, Jain and colleagues synthesized novel NO-releasing NSAID derivatives of aspirin and ibuprofen that possessed a tyrosol linker between the NSAID and the NO-releasing moiety (PROLI/NO).93 Though, when Jain and co-workers tested ester intermediates that did not possess PROLI/NO group (49 and 50), they still showed in vitro and in vivo anti-inflammatory activity greater than the parent compounds and that raised a question over the need of NO-releasing moiety in the compounds. The augmented activity of the ester intermediates was attributed to their higher lipophilicity compared with the parent NSAIDs. Nitroxyl (HNO) is a one-electron reduced and protonated congener of NO, which has significant therapeutic potential.94 Many biological activities of HNO and NO are overlapping95 with numerous early studies accounting that biological actions of HNO could be due to its conversion into NO.96 Although over the years rigorous studies have indicated that the chemistry of HNO and NO are distinct, and currently, there is little doubt that different biology of both the species is because of their different chemical nature.95 A key difference in the pharmacological actions of HNO and NO is that the former preferentially shows venous dilation, while the latter exhibits both venous and arterial dilations equally.97, 98 Based on the evidence that HNO diminishes platelet aggregation, prerequisites against myocardial infarction, and improves contractility led Basudhar et al. to synthesize a diazeniumdiolate-based HNO-releasing aspirin.99 Even though, NO-donating NSAIDs have been described in the past, this is the first prototype of an HNO-releasing NSAID. Such developed conjugates, O2 -(acetylsalicyloyloxymethyl)1-(N,N-diethylamino)-diazen-1-ium-1,2-diolate (51) and O2 -(acetylsalicyloyloxymethyl)-1-(Nisopropylamino)-diazen-1-ium-1,2-diolate (52) retained the anti-inflammatory effects of aspirin while decreasing gastric toxicity. Besides providing safety against stomach ulceration, the HNO– NSAID hybrids inhibited COX-2 and glyceraldehyde 3-phosphate dehydrogenase activity and Medicinal Research Reviews DOI 10.1002/med

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induced noteworthy sarcomere shortening on murine ventricular myocytes compared to control. Collectively, these anti-inflammatory and contraction ability effects indicate the ability of HNO–NSAIDs in the treatment of inflammatory diseases and cardiac failure. 5. Sulfohydroxamic Acids Sulfohydroxamic acids (R-SO2 NHOH) are chemical entities that act as dual NO/HNOreleasing agents. A novel series of indomethacin, naproxen, and ibuprofen derivatives that could release NO and HNO were synthesized by Huang and associates.100 In these compounds, an acidic group of NSAIDs was covalently linked to the sulfohydroxamic acid moiety (CH2 CH2 SO2 NHOH) via a two-carbon ethyl spacer. All the ester conjugates were found to be selective inhibitors of COX-2, showed lessened ulcerogenicity, and released the cytoprotective NO. Naproxen and ibuprofen conjugates 53 and 54–55, respectively, surfaced as the exceptionally potent anti-inflammatory agents with activity superior to their parent NSAIDs. Although aforementioned studies have shown the efficacy and safety of NO–NSAIDs in various inflammatory conditions, particularly in osteoarthritis,65, 69, 101–103 none of them has been granted regulatory approval, because the safety advantages of NO–NSAIDs over the parent drugs have not yet been satisfactorily ascertained.104 NO-releasing NSAIDs appeared to be well tolerated in the small intestine of rodents and in clinical studies also, they have produced significantly reduced small intestinal damage than the parent NSAIDs.15 6. H2 S-Releasing NSAIDs Wallace et al. reported H2 S-releasing diclofenac derivative ATB-337 (56).105 At a dose of 10 μM/kg, both diclofenac and its derivative ATB-337 (56) suppressed COX-2 activity by >95%. Repeated administration of diclofenac resulted in extensive small intestine injuries, while ATB337 produced >90% less small intestine damage than diclofenac. In the subsequent study, Wallace and co-workers further documented H2 S-releasing derivatives of naproxen, ATB-345 (57) and ATB-346 (58).106 The derivative ATB-346 suppressed gastric PGE2 synthesis as efficiently as naproxen and more efficiently than ATB-345, but produced negligible GI injuries as compared to naproxen. Twice a day oral administration of naproxen resulted in a significant reduction of paw volume on day 21, but not on day 14. On the contrary, treatment with ATB-346 produced a significant reduction of paw volume on days 14 and 21. Unlike naproxen, ATB-346 did not raise blood pressure in hypertensive rats.106 In rats, ATB-346 decreased the gastric acidity by 50% while increasing mean pH of gastric juice from 1.48 to 2.11 and decreasing the secretion volume by 82%.107 It is now established that proton-pump inhibitors (PPIs) when administered with NSAIDs, augment the small intestine injury by inducing dysbiosis, particularly by decreasing the population of Bifidobacteria.108 ATB-346, when coadministered with a PPI or low-dose aspirin, retained its favorable profile in the small intestine.77, 104 Other than the enteric bacteria, bile and enterohepatic circulation are two critical factors for the NSAID-induced enteropathy. After absorption, NSAIDs experience a glucuronidation process in the liver, which is followed by their secretion into bile. Bacterial β-D-glucuronidase then deconjugates the NSAID-glucuronide complex to facilitate their reabsorption in the ileum. Apart from dysbiosis, this process contributes significantly to the NSAID-induced enteropathy.107 A single dose of ATB-346 produced a serum level of 53 μM, while in the same conditions naproxen showed a serum level of 98 μM. ATB-346 metabolizes to release naproxen, but relatively a decreased level of naproxen in bile was observed.77 After 4 hr administration of test drugs, ATB-346 displayed a significantly less bile naproxen level of 0.5 μM when compared with the bile naproxen level of 1.5 μM shown by naproxen-treated rats.77 The ratio of naproxen glucuronide after a single dose of test drugs was found to be 22:10 in the naproxen- and ATB-346-treated rats, respectively. This ratio was changed to 32:9 after an administration of Medicinal Research Reviews DOI 10.1002/med


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four doses of test drugs.77 Thus, the biliary level of naproxen-glucuronide was reduced by 72% in ATB-346-treated group when compared to the naproxen-treated group while retaining the anti-inflammatory potency of ATB-346.77, 104 In an attempt to improve the potency and cardiovascular safety of NO/H2 S–NSAIDs, Lazzarato et al. employed a new methodology and synthesized ((R-oxy)carbonyl)oxy)methyl esters of aspirin possessing either NO- or H2 S-releasing groups.109 All the ester conjugates inhibited collagen-induced platelet aggregation of human PRP. The NO-/H2 S-donating intermediates were able to relax contracted rat aorta strips via NO- and H2 S-dependent mechanisms. Intermediate structure 3-(4-hydroxyphenyl)propane-1,2-diyl dinitrate (59) was found to be the most potent vasodilator with EC50 of 0.13 μM, while H2 S-releasing conjugate ((2-(4-(3-thioxo3H-1,2-dithiol-5-yl)phenoxy)ethoxy)carbonyloxy)methyl 2-(acetyloxy)benzoate (60) displayed highest antiaggregatory effect with IC50 of 16 μM. 7. Dual H2 S- and NO-Releasing NSAIDs Kodela et al. synthesized novel aspirin hybrids possessing both NO- and H2 S-releasing moieties.110 Among the compounds tested, 4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl 2-((4(nitrooxy)-butanoyl)oxy) benzoate (61) was found to be the most potent hybrid that displayed anti-inflammatory activity equipotent to aspirin, determined in the carrageenan-induced rat paw edema model. Recently, Kodela and fellow workers further developed dual NO- and H2 Sreleasing NOSH–naproxen (62) and NOSH–sulindac (63) and evaluated for anti-inflammatory effects.111 In the carrageenan-induced rat paw edema model, both compounds exhibited significant anti-inflammatory properties. Naproxen- and sulindac-treated animals showed a substantial decrease in PGE2 levels from 95 pg/mg in the control groups to 15 pg/mg and 12 pg/mg, respectively. Treatment with NOSH–naproxen and NOSH–sulindac decreased PGE2 levels to 35 and 29 pg/mg, respectively. The increase in paw volume of the animals receiving NOSH–naproxen and NOSH–sulindac was less than those receiving naproxen and sulindac, respectively. Taken together, H2 S is an endogenous anti-inflammatory molecule that has shown mucosal integrity, repair, and resolution of inflammation, which can be exploited in therapeutic applications.112 H2 S-releasing NSAIDs demonstrate anti-inflammatory potency higher or similar to the parent drugs while protecting the gastric mucosa. The striking difference between H2 S-releasing and other NSAIDs is that H2 S-releasing NSAIDs produce negligible small intestine toxicity/enteropathy than the parent compounds and also exhibit reduced cardiovascular adverse effects. B. Antioxidant–NSAID Hybrids 1. TEMPO–NSAIDs Antioxidants are advantageous not only in several inflammatory conditions but also in oxidative stress.113, 114 The nitroxides are also widely known to possess such beneficial properties.113 The HNO radical bearing 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy (4OH-TEMPO/TEMPOL) is a superoxide dismutase mimetic agent and/or potent antioxidant against oxidative stress induced by peroxides and radiations.113, 115–117 The electrochemical properties of TEMPOL makes it excellent candidate for scavenging reactive oxygen species while reducing the oxidative stress.118 Flores-Santana and associates evaluated anti-inflammatory effects of TEMPO–NSAIDs, TEMPO–aspirin (64), and TEMPO–indomethacin (65) (Fig. 7) by measuring production of PGE2 and LTB4 .113 They also performed carrageenan-induced foot paw edema and ulcerogenic assays in mice.113 Study found that TEMPO–aspirin was as well tolerated as the aspirin, Medicinal Research Reviews DOI 10.1002/med

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Figure 7. Antioxidant–NSAID (64–71), phospho-NSAID (72–74), anticholinergic–NSAID (75–79), and AChEI– NSAID (80) derivatives.



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while TEMPO–indomethacin displayed eightfold improvement over indomethacin and showed remarkably less gastric toxicity than the parent NSAIDs. Both TEMPO–aspirin and TEMPO– indomethacin suppressed production of PGE2 and LTB4 in A549 cells. In the in vivo antiinflammatory assay, TEMPO–indomethacin exhibited ED50 of 3.2 mg/kg, while indomethacin demonstrated ED50 of 4.2 mg/kg, and consequently, TEMPO–indomethacin was about 15% more potent compared with indomethacin. In general, these TEMPO-modified NSAIDs either retained or augmented the COX inhibitory effects and the nitroxide part of the molecule was helpful in scavenging the superoxide anion.113

2. Alcoholic/Phenolic Antioxidant–NSAID Hybrids Antioxidants can scavenge the free radicals and reactive oxygen species associated with the origin of peptic ulcer. Alcoholic and phenolic compounds of natural origin are widely known for their antioxidant, anti-inflammatory, and analgesic properties. Conjugation of these alcoholic and phenolic compounds with classical NSAIDs not only enhances the potency of NSAIDs but also imparts gastrosparing characters. A variety of natural antioxidant–NSAID derivatives (66–71) developed in recent years as improved and safer NSAIDs are presented in Figure 7. Following the aforesaid approach, Menon and associates synthesized diclofenac prodrugs with guaiacol, eugenol, thymol, vanillin, sesamol, umbelliferone, and menthol using glycolic acid as a spacer.119 Results of in vivo anti-inflammatory and analgesic assays revealed that diclofenac– sesamol ester (66) was the most potent among all the prodrugs and also demonstrated reduced ulcerogenicity compared with the diclofenac. Biphenylacetic acid is an active metabolite of potent NSAID fenbufen and is believed to be more efficacious than the parent drug. Madhukar and colleagues conjugated two anti-inflammatory moieties, that is, 4-biphenylacetic acid and quercetin tetramethyl ether as gastrosparing NSAID, employing a hybrid synthesis approach.120 The resultant prodrug 67 was stable against chemical hydrolysis, while it hydrolyzed rapidly in plasma to liberate the parent drug moieties. Moreover, the prodrug 67 showed significant analgesic and anti-inflammatory activity and also proved to be less ulcerogenic than the parent drug. Aiming to retard the gastric toxicity associated with the use of NSAIDs, Sawraj et al. synthesized conjugates of indomethacin with antioxidants, namely naringenin and hespertin by esterification method.121 The synthesized conjugates not only retained the anti-inflammatory activity but also decreased the ulcerogenic side effects of indomethacin. Both the synthesized indomethacin–naringenin (68) and indomethacin–hespertin (69) conjugates displayed in vivo anti-inflammatory and analgesic activities superior to that of indomethacin with 69 being the slightly more active than 68. Pursuing the antioxidant–NSAID hybrids approach, Redasani et al. prepared prodrugs of ibuprofen with menthol, thymol, and eugenol.122 All the synthesized prodrugs showed anti-inflammatory activity superior to the ibuprofen with vastly improved ulcerogenic profile and among these prodrugs, ibuprofen–menthol conjugate (70) emerged as the lead antiinflammatory candidate, which could be considered for further development as a gastrosparing NSAID. Recently, Chandiran and co-workers synthesized ibuprofen–antioxidant (thymol, guaiacol, eugenol, and menthol) hybrids with and without a spacer (CH2 COO).123 All the synthesized ibuprofen–antioxidant conjugates not bearing spacer between the NSAID scaffold and antioxidant moiety showed in vivo anti-inflammatory activity superior to the ibuprofen, while their analgesic activity was also found to be equal to that of ibuprofen. Among the conjugates screened, the ibuprofen–eugenol ester (71) demonstrated anti-inflammatory and analgesic activity higher than the other counterparts. All the conjugates also displayed improved gastric tolerability with ulcerogenic potential lower than ibuprofen. Conversely to the conjugates without a spacer, the conjugates those possessed a spacer showed less activity. Medicinal Research Reviews DOI 10.1002/med

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C. Phosphatidylcholine-Conjugated NSAIDs GI mucosa is hydrophobic in nature and protects the underlying epithelium from gastric acid and other luminal toxins.124 This hydrophobic nonwettable property of GI mucosa is caused by surfactant like phospholipids, probably a single layer, coating the surface of the mucus gel layer.124, 125 Thus, surface-active phospholipids act as a barrier between the luminal contents and epithelium.124 Various studies have suggested that agents, such as NSAIDs, H. pylori, and bile salts attenuate the hydrophobic property of the GI mucosa, whereas this property of GI mucosa is enhanced by protective agents, such as prostaglandins.124–126 Phosphatidylcholine represents the most abundant and surface-active form of gastric phospholipids.124 NSAIDs get chemically associated with phosphatidylcholine and then destabilize it from the surface of the mucus gel layer, rendering the GI mucosa more susceptible toward injury.124, 127 NSAIDs, particularly amphiphiles disrupt the GI mucosa by partitioning into both the extracellular and membrane phospholipid layers, modulating their physical properties. This leads to the formation of membrane pores in the mucosa, facilitating back diffusion of luminal acid.128–130 NSAIDs that undergo extensive enterohepatic cycling disrupt the surface-active phospholipid layer to a greater degree, thereby producing more toxicity to the GI mucosa.124 Phosphatidylcholine-associated NSAIDs is an approach to maintain the hydrophobic surface barrier of the GI tract to protect the GI mucosa against the NSAID-induced toxicity while maintaining or enhancing therapeutic activity of NSAIDs. Phosphatidylcholine-associated aspirin PL2200, which has received FDA approval, was developed by PLx Pharma Inc., USA. PL2200 has antiplatelet efficacy equivalent to aspirin, while it decreases gastroduodenal ulcers by 70% when compared with the aspirin.124, 131, 132 When phosphatidylcholine-associated aspirin was coadministered with celecoxib, it produced negligible gastric injury/bleeding and preserved the hydrophobic barrier. Contrastingly, coadministration of aspirin with celecoxib exacerbated gastric injury and bleeding in rats.21, 133 Although aspirin and phosphatidylcholine-associated aspirin inhibited gastric mucosal PGE2 equally, coadministration of aspirin with celecoxib slowed down the experimentally induced gastric ulcers healing, whereas the combination of phosphatidylcholine-associated aspirin and celecoxib displayed gastric ulcer healing rate comparable to controls.21, 133 Phosphatidylcholine-associated ibuprofen (PL1100; PLx Pharma Inc.), at an antiarthritic dose of 2400 mg/kg for 6 weeks, has shown bioavailability and therapeutic potency similar to the ibuprofen while reducing gastroduodenal erosions and ulcers.134–136 In patients aged >55 (with a mean age of 64 years), ibuprofen-treated patients had a significantly greater absolute change in Lanza scores (mucosal hemorrhages + erosions + ulcers) and were 3.7 times more likely (or a 270% increased risk) to develop multiple gastroduodenal erosions (Lanza score >2) than the phosphatidylcholine-associated ibuprofen-treated patients.124 Hence, these findings indicate a potential therapeutic use of phosphatidylcholine-conjugated NSAIDs in both prevention of mucosal injury and treatment of preexisting ulcers.

D. Phospho-NSAIDs The reports of phospho-NSAIDs do not describe the role of the phospho/phosphate group in phospho-NSAIDs or their key characteristics that led researchers to synthesize phosphoNSAIDs. However, in one report inventors stated that the modification at the carboxylic group of NSAIDs, which is critical for toxicity, might provide safer NSAIDs.137 It may be another possibility that while designing phospho-NSAIDs, researchers might have thought to mimic the some structural part of the phosphatidylcholine-associated NSAIDs to develop phospho-NSAIDs. In this approach, Huang et al. screened the anti-inflammatory potency and safety of a new series of phospho-NSAIDs, namely phospho-aspirin (MDC-22) (72), Medicinal Research Reviews DOI 10.1002/med


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phospho-ibuprofen (MDC-917) (73), and phospho-sulindac (OXT-328) (74) (Fig. 7) in the rat adjuvant arthritis model and studied their mechanism of action.138 The level of cytokines was determined by ELISA, while activation of NF-κB was measured by immunohistochemistry. All three phospho-NSAIDs displayed less GI toxicity than their parent compounds and showed strong anti-inflammatory properties while remarkably suppressing joint inflammation and edema. Phospho-aspirin and phospho-ibuprofen at equimolar doses of parent drugs induced 68% and 60% less GI damage than aspirin and ibuprofen, respectively. Similar results of GI safety have been reported for phospho-sulindac in other report.137 The phospho-NSAIDs had a wide-ranging though consistent effect on the expression of related cytokines. They decreased the expression of IL-6 and IL-1β, whereas increased the expression of IL-10 levels in rat plasma and cultured cells. Phospho-NSAIDs, except phospho-aspirin decreased PGE2 production in vitro, whereas phospho-aspirin (on the contrary to aspirin) demonstrated the same effect in vivo. Phospho-aspirin inhibited NF-κB activation and Jurkat T-cell proliferation while suppressing inflammation and bone resorption. The authors noticed that phospho-aspirin showed higher potency but had dissimilar effects upon inflammatory mediators compared with the aspirin. Xie et al. studied the metabolism of phospho-aspirin (MDC-22) in the liver and intestinal microsomes from mouse, rat, and human.139 The authors noticed that phospho-aspirin was deacetylated to phospho-salicylic acid, which was then regioselectively oxidized into 3-OHphospho-salicylic acid and 5-OH-phospho-salicylic acid. The 3- and 5-OH-phospho-salicylic acid later hydrolyzed to yield salicylic acid. Phospho-aspirin was found to be more stable in human liver or intestinal microsomes compared to those from mouse or rat because of its slowest deacetylation in human microsomes. Among the cytochrome P450 (CYP) isoforms evaluated, CYP2C19 and 2D6 were the most active toward phospho-salicylic acid. In contrast to phospho-salicylic acid, phospho-aspirin could not be directly oxidized by CYPs and liver microsomes, indicating that the acetyl group of phospho-aspirin abrogates its oxidation by CYPs. Xie and co-workers also investigated the metabolic reactions of phospho-ibuprofen in cultured cells, liver microsomes, and mice.140 It was seen that cultured cells had negligible effects on phospho-ibuprofen but in liver microsomes and mice, phospho-ibuprofen underwent extensive metabolic conversion to generate 1-OH-phospho-ibuprofen and carboxyl-phosphoibuprofen, which were hydrolyzed into 1-OH-ibuprofen and carboxyl-ibuprofen, respectively. Phospho-ibuprofen could also be hydrolyzed to ibuprofen, which could further produce 2-OHibuprofen, carboxyl-ibuprofen, and ibuprofen glucuronide. In a single dose oral administration of phospho-ibuprofen, ibuprofen, and ibuprofen glucuronide were generated as the main metabolites and they showed Cmax of 530 and 215 μM, Tmax of 1 and 2 hr, elimination t1/2 of 7.7 and 5.3 hr, and area under the concentration–time curve (0–24 hr) of 1816 and 832 μM × hr, respectively. Intact phospho-ibuprofen was not detected in plasma and generated the same metabolites in plasma as classical ibuprofen, but with much lesser extent, possibly responsible for the increased safety of phospho-ibuprofen. Xie et al. also investigated the metabolism of phospho-sulindac (OXT-328) in cultured cells, liver microsomes and cytosol, intestinal microsomes, and in mice. Pharmacokinetics and biodistribution of phospho-sulindac were also studied in mice.141 They observed that phospho-sulindac underwent reduction and oxidation to give phospho-sulindac sulphide and phospho-sulindac sulphone. Phospho-sulindac sulphide and phospho-sulindac sulphone on hydrolysis released sulindac, which produced sulindac sulphide and sulindac sulphone, all of which were glucuronidated. Phospho-sulindac was extensively metabolized in the liver and intestinal microsomes, but cultured cells transformed only 10% of it to phospho-sulindac sulphide and phospho-sulindac sulphone. When administered orally in mice, phospho-sulindac was rapidly absorbed, metabolized, and distributed to the blood and other tissues. In blood, phospho-sulindac was hydrolyzed significantly into three major metabolites; sulindac, sulindac Medicinal Research Reviews DOI 10.1002/med

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sulphide, and sulindac sulphone. Sulindac displayed highest Cmax , while sulindac sulphone showed maximum t1/2 . In gastroduodenal wall of mice, 71% of phospho-sulindac was found to be intact, which explained the gastrosparing characters of it. Xie et al. further studied the metabolism of phospho-ibuprofen (MDC-917) and phospho-sulindac (OXT-328) by major human CYPs and flavin monooxygenases (FMOs).142 Oxidation of phospho-ibuprofen was catalyzed by CYP isoforms CYP1A2, 2C19, 2D6, and 3A4, but not of ibuprofen. On the contrary, CYP2C9 oxidized ibuprofen, but not phospho-ibuprofen. Phospho-sulindac was oxidized by all five CYPs isoforms, but not sulindac. Among the CYP isoforms tested, CYP3A4 and 2D6 most actively catalyzed the oxidation of phospho-ibuprofen and phospho-sulindac, respectively. Phospho-sulindac and sulindac were oxidized by FMOs, but not phospho-ibuprofen or ibuprofen. Phospho-sulindac was more susceptible toward FMOs than sulindac, demonstrating that phospho-sulindac is a favored substrate of FMOs. The susceptibility of phospho-NSAIDs to CYP/FMO-regulated metabolic transformation was also replicated in their rapid oxidation by human and mouse liver microsomes, which possessed a full complement of CYPs and FMOs. The greater activity of CYPs toward phospho-ibuprofen and phospho-sulindac compared with traditional NSAIDs might have been caused by their superior lipophilicity, an important criteria for CYP affinity. Recently, Mattheolabakis et al. formulated phospho-sulindac (OXT-328) in a pluronic hydrogel form and evaluated topically in LEW/crlBR rats with Freund’s adjuvant-induced arthritis.143 Results of topical administration study indicated that pluronic hydrogel of phosphosulindac suppressed arthritis by 56–82%, improved the locomotor activity of the rats 2.1–4.4 times, suppressed synovial inflammation, bone resorption, cartilage damage, NF-κB activation, and COX-2 expression, but not plasma IL-6 and IL-10 levels. In general, dermal application of phospho-sulindac was efficacious and safe in the treatment of Freund’s adjuvant-induced arthritis, had an encouraging pharmacokinetics profile, and perhaps acts by inhibiting key proinflammatory mediators. E. Anticholinergic–NSAID and AChEI–NSAID Hybrids NSAID-induced gastric toxicity correlates with the deceased levels of mucosal prostaglandins, raised gastric motility, decreased mucosal blood flow, hypoxia, and degeneration of the mucous bicarbonate barrier facilitating back diffusion of pepsin and hydrogen ions from the lumen into the mucosal layer. Anticholinergics can slow down gastric motility, decrease gastric acid secretions, and maintain optimum blood flow. Thus, the conjugation of an anticholinergic moiety with NSAIDs may convey gastrosparing characters in the resultant hybrid molecules. A number of anticholinergic–NSAID hybrids (75–79) have been synthesized and accounted as the improved NSAIDs (Fig. 7). In one such approach, Halen and associates modified 4-biphenylacetic acid and flurbiprofen NSAIDs into N,N-disubstituted amino-ethyl ester derivatives, which fulfilled the structural prerequisites for these compounds to have anticholinergic activity in the intact form.144 The (1-piperidinyl)ethyl substituted 4-biphenylacetic acid and flurbiprofen derivatives 75 and 76, respectively, displayed anti-inflammatory activity greater than the parent compounds. These compounds also demonstrated vastly improved gastric safety profiles and induced stomach lesions far less than the parent compounds. Other compounds substituted with (dimethylamino)ethyl, (diethylamino)ethyl, (1-pyrrolidino)ethyl, and (4-morpholino)ethyl groups showed weak activity. Continuing with their earlier study, Halen and co-workers further synthesized N,N-disubstituted aminoethanol ester derivatives of indomethacin bearing structural resemblance to the aminoethanol ester class of anticholinergics.145 The analog 77 bearing (dimethylamino)ethyl substitution displayed anti-inflammatory activity superior to indomethacin. It also showed analgesic activity equipotent to indomethacin while producing stomach toxicity less than indomethacin. Other indomethacin analogs possessing Medicinal Research Reviews DOI 10.1002/med


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(diethylamino)ethyl, (1-pyrrolidino)ethyl, (1-piperidino)ethyl, and (4-morpholino)ethyl substitutions demonstrated feeble activity. Contemporary to the previous study, Halen and fellow workers additionally synthesized N,N-disubstituted aminoalcohol ester derivatives of ibuprofen and ketoprofen.146 From the series of prodrugs synthesized, (dimethylamino)ethyl-substituted ketoprofen ester (78) appeared as the lead anti-inflammatory candidate with UI less than that of ibuprofen and ketoprofen. Going along with their previous research, Halen et al. further synthesized aminoalcohol esters of naproxen and 6-methoxy-2-napthylacetic acid (6-MNA) bearing structural resemblance to the aminoalcohol ester class of anticholinergics.147 All the synthesized prodrugs displayed enough resistance against chemical hydrolysis, while hydrolyzed readily in 80% human plasma to release the promoieties. Synthesized prodrugs demonstrated greatly improved gastric safety profiles and when evaluated in a carrageenan-induced rat paw edema assay, naproxen analog (79) bearing (1-piperidinyl)ethyl group showed the utmost inhibition of edema. Anticholinergics are antisecretory drugs that reduce gastric and salivary secretions. However, two other classes of antisecretory drugs, namely PPIs and histamine H2 receptor antagonists (H2 RAs) that are currently being coprescribed with NSAIDs to reduce NSAID-induced toxicity have been a failure to the some extent, particularly in NSAID-induced enteropathy. In fact, PPIs exacerbate the NSAID-induced toxicity in the small intestine.15 Moreover, anticholinergics have other side effects as well, such as inhibition of sweating, dry mouth, urinary retention, and central anticholinergic syndrome. The inhibitory effect of anticholinergics on sweat glands increases the basal metabolic rate, leading to rise in body temperature. Taken together, anticholinergic agents offer a little promise to be developed as safer and potential NSAIDs. Acetylcholinesterase inhibitors (AChEIs) have implications in the treatment of severe inflammation associated with rheumatoid arthritis,148 neuroinflammation related to Alzheimer’s disease,149–151 and Myasthenia Gravis.152 The AChEIs are assumed to suppress inflammation through a cholinergic anti-inflammatory pathway, a mechanism by which the vagus nerve mediates the production and release of TNF and other cytokines.153, 154 Therefore, it is assumed that NSAID–AChEI hybrid molecules can potentiate the anti-inflammatory activity by activating the cholinergic anti-inflammatory pathway. Young et al. synthesized ester and ester carbonate series of diclofenac, indomethacin, ibuprofen, and naproxen derivatives possessing cholinergic functions (–CO–O–CH2 CH2 X(CH3 )3 ; X = C, Si, N+ ).155, 156 The cholinergic functions act as the bioisosteres of choline and inhibit AChE.155, 157 Among the compounds tested, diclofenac derivative 80 (Fig. 7) from the ester carbonate series appeared as the most potent AChEI with IC50 of 0.51 μM. The diclofenac derivative 80 also inhibited 2-chloro-ethyl-ethyl sulfide (CEES) and 12-O-tetradecanoylphorbol-13-acetate (TPA) induced vesicant/edema in mice by 90% and 24%, respectively. At the same time, diclofenac suppressed CEES- and TPA-induced edema by 17% and 58%, correspondingly. However, there is a little hope that AChEIs can be useful as safer NSAIDs as they increase gastric acid secretions and gastric motility. This case seems in contrast to the prerequisites for safer NSAIDs. Moreover, accumulation of acetylcholine causes bradycardia through vagal effects, leading to decreased cardiac output and blood pressure. Contraction of bronchial smooth muscles by AChEIs can cause bronchoconstriction, which would be more aggravated by increased bronchial secretions. The use of AChEIs has also been associated with vomiting, anorexia, and diarrhea. F. Microsomal Prostaglandin E2 Synthase Inhibitors COX enzymes catalyze the conversion of arachidonic acid into prostanoids, such as PGE2 , prostacyclin (PGI2 ), PGD2 , PGF2α , and TXA2 via PGH2 . NSAIDs inhibit the activity of Medicinal Research Reviews DOI 10.1002/med

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Figure 8.

Microsomal prostaglandin E2 synthase-1 inhibitors (mPGES-1) inhibitors (81–83).

COX-1 and COX-2, which in turn suppresses the production of PGE2 to modify the inflammatory conditions. However, long-term use of NSAIDs is also associated with the nonselective inhibition of antithrombotic PGI2 and prothrombotic TXA2 , which is responsible for the unfavorable effects of NSAIDs, including cardiovascular adverse effects. Microsomal prostaglandin E2 synthase-1 (mPGES-1), a downstream PG synthase, particularly catalyzes the biosynthesis of COX-2-derived PGE2 from PGH2 , and thus, it is considered as an important therapeutic target for the novel NSAIDs with reduced toxicity.158 In this direction, Shinji et al. found that MK-886 (3-[1-(p-chlorobenzyl)-5-(isopropyl)3-t-butylthiomindol-2-yl]-2,2-dimethylpropanoic acid) (81) (Fig. 8) inhibits IL-1β stimulated increase in PGE synthase activity by 86.8% in gastric fibroblasts.159 MK-886 derivatives 82 and 83 (Fig. 8) have shown IC50 s of 0.007 and 0.003 μM, respectively, against mPGES-1, while IC50 of MK-886 against mPGES-1 was found to be 1.6 μM.160 MK-886 also suppressed LT synthesis in the intact leukocytes with an IC50 of 2.5 nM.161 MK-886 inhibits IL-1β-stimulated VEGF release in gastric fibroblasts totally to basal levels.159 However, VEGF plays a key role in ulcer healing by promoting angiogenesis54, 162 and its release is stimulated by COX-2 and mPGES-1.52 According to J. L. Wallace, there is a strong possibility that selective inhibition of mPGES-1 would delay the ulcer healing same as that of the selective COX-2 inhibitors.33 Moreover, in a knockout studies, mice deficient with mPGES-1 have shown hypertension, impaired natriuretic responses, and worsened cardiac parameters163 on administration of high salt diet,164 angiotensin II,164–166 aldosterone,167 or DOCA salt.168 Knockdown of mPGES1 has also been associated with a detrimental left ventricular remodeling after myocardial infarction.169 G. Amino Acid–NSAID and Carbohydrate–NSAID Derivatives Amino acids and carbohydrates have been widely used as the promoieties of the NSAID esters because of their low partition coefficients and superior GI tolerability. Conjugation of amino acids and carbohydrates with NSAIDs improves solubility, enhances bioavailability, and imparts gastrosparing properties in the resultant compounds. Various amino acid– NSAID and carbohydrate–NSAID derivatives (84–96) prepared and reported as the superior NSAIDs in the recent years are presented in Figure 9. Intending to improve the pharmacological profile by means of decreasing the lipophilicity, Shalaby and co-workers synthesized conjugates of diclofenac with different amino acids and screened for anti-inflammatory and analgesic activities.170 In the carrageenan-induced pleurisy assay, animals treated with diclofenac–glycylglycine methyl ester (84) exhibited least edema progression. Though, in the electric stimulation test for analgesic activity, a diclofenac–L-methinine ester (85) was found to be more potent than the ester conjugate 84 and the parent compound diclofenac. Medicinal Research Reviews DOI 10.1002/med


Figure 9.

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Amino acid–NSAID and carbohydrate–NSAID derivatives (84–96).


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Aspiring to potentiate the anti-inflammatory and analgesic activity of diclofenac, Abo-Ghalia and fellow workers synthesized diclofenac conjugates of amino acids, namely sarcosine, βalanine, D-leucine, and D-phenylalanine.171 From the series of compounds evaluated, thiomimic sarcocine–diclofenac conjugate (86) emerged as the lead compound. The compound 86 also showed highest activity in the electric stimulation test for the analgesic activity. Ketorolac is a member of heterocyclic acetic acid derivatives, which is prescribed for the short-term management of moderate to severe pain. In an effort to improve the bioavailability and gastric safety, Mishra and associates synthesized amide prodrugs of ketorolac, wherein amino acids (glycine, L-phenylalanine, L-tryptophan, L-valine, L-isoleucine, L-alanine, L-leucine, L-glutamic acid, L-aspartic acid, and β-alanine) were linked to the ketorolac.172 From the series of compounds tested for in vivo anti-inflammatory and analgesic activity, ketorolac–acetylated aspartic acid conjugate (87) emerged as the most potent amide conjugate that showed maximum edema inhibition. All the synthesized prodrug conjugates displayed improved solubility, better absorption, and lower ulcerogenic indices than ketorolac. Another synthetic analog of ketorolac, named ketogal (ketorolac conjugated with D-galactose) (88) was synthesized in the lab of Curcio and co-workers.173 In the pharmacological screening assay, ketogal exhibited analgesic effects stronger than those produced by ketorolac. The authors also measured the effects of ketogal on carrageenan-induced paw edema in mouse and found that ketogal remarkably reduced the paw edema in a time- and dose-dependent manner. Moreover, ketogal also improved the ulcerogenic profile compared with the ketorolac. Indomethacin is a nonselective inhibitor of COX-1 and COX-2 enzymes with strong anti-inflammatory activity. Zhang and associates with the aim of improving the gastric safety, prepared indomethacin–D-glucosamine conjugates.174 From the set of compounds evaluated in biological assay, ester conjugates 89 and 90 demonstrated noteworthy anti-inflammatory activity with reduced ulcerogenicity. Going along with the conventional approach of developing profen NSAIDs, Zhao and aides synthesized prodrugs of ibuprofen with α-methyl, ethyl, and propyl glucopyranosides.175 The compound 91 was found to be the most potent analgesic agent, while compound 92 emerged as the most active anti-inflammatory agent. Later on, to improve the bioavailability and sustain release properties of flurbiprofen, Mishra et al. synthesized a series of amide prodrugs of flurbiprofen with amino acids, namely glycine, L-phenylalanine, L-tryptophan, L-valine, L-isoleucine, L-alanine, L-leucine, L-glutamic acid, L-aspartic acid, and β-alanine.176 The study disclosed that the introduction of either aliphatic side chain or aromatic group in the compounds raised the partition coefficients, which in turn decreased the dissolution and hydrolysis rates that could be suitable to sustain release delivery of drugs. In vivo biological evaluation studies revealed that the amide congener of flurbiprofen with aspartic acid (93) was highly potent analgesic and anti-inflammatory agent. Mefenamic acid or 2-(2,3-dimethylphenyl)aminobenzoic acid is an anthranilic acid derivative, indicated for use in the acute inflammation and pain. Rasheed et al. described the synthesis of amide prodrugs of mefenamic acid with histidine and tryptophan.177 They assumed that the amidation of carboxyl function of mefenamic acid will impart gastrosparing characters in the prodrugs. In the carrageenan-induced rat paw edema assay, mefenamic acid–histine prodrug (94) exhibited edema inhibition superior to mefenamic acid, while in the thermal stimulusinduced rat tail flick analgesic assay, 94 demonstrated analgesic activity comparable to that of mefenamic acid. Galanakis and co-workers reported the synthesis of amide conjugates of NSAIDs (indomethacin, diclofenac, tolfenamic acid, flufenamic acid, ibuprofen, naproxen, and ketoprofen) and L-cysteine ethyl ester for potent anti-inflammatory properties.178 Among the conjugates tested, indomethacin–L-cysteine ethyl ester (95) surfaced as the highly active antiinflammatory agent that reduced carrageenan-induced paw edema volume with the maximum degree. Aspiring to develop a topical drug-delivery system of NSAIDs, Li et al. developed multifunctional supramolecular nanofibers/hydrogels of NSAIDs (aspirin, ibuprofen, naproxen, Medicinal Research Reviews DOI 10.1002/med


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and flurbiprofen) with small peptides.179 The authors observed that covalent linking of PhePhe with NSAIDs produced conjugates that were able to self-assemble in the water to form a molecular nanofibers/hydrogels. Naproxen–peptide hydrogelator (96) produced a hydrogel at a critical concentration of 0.2 wt% at pH 7.0. Results indicated that after conjugation with amino acids or small peptides, NSAIDs displayed improved selectivity to the targets and maintained their efficacy as well. This approach may lead to the development of novel hydrogels of NSAIDs for topical or dermal applications. Although conjugation of NSAIDs with polar biomaterials, such as amino acids and carbohydrates can improve the bioavailability while decreasing the partition coefficients of the resultant drugs. However, all the reported studies concerning to amino acid–NSAIDs and carbohydrate–NSAIDs are too preliminary in nature and there is a doubt that amino acids or carbohydrates would act as a protective intervention against NSAID-induced toxicity. Apart from this, these conjugates are synthesized either as the ester or amide prodrugs while masking the acidic group of NSAIDs. However, prodrugs have been a clinical failure, as systemic administration of NSAIDs also produces GI toxicity15 that we have discussed in detail in the later part of the manuscript. NSAIDs that are excreted into bile can be refluxed back into the stomach to cause the toxicity. Moreover, NSAID-induced enteropathy, which is caused by deconjugation of bile acids or conversion of primary bile acids to secondary bile acids by bacterial enzymes, and enterohepatic recirculation of NSAIDs (bacterial β-D-glucuronidase deconjugates the NSAIDglucuronides, facilitating reabsorption in the ileum)107 have not been addressed by these agents, thus, making this approach less significant in the direction of safer NSAIDs. Additionally, existing NSAIDs suffer from GI toxicity rather than solubility and/or bioavailability shortcomings. Interestingly, cysteine, which acts as a precursor for H2 S synthesis,112 could be a useful amino acid for conjugation with the NSAIDs. Then again, when we have direct H2 S-releasing agents or H2 S-releasing agents that can be directly conjugated with the NSAIDs, weaken the prospect of cysteine–NSAID conjugates.

H. COX and LOX Inhibitors 1. Development of Classical NSAIDs as Selective COX-2 Inhibitors Over the past few years, the roles of COX-1 and COX-2 in the inflammation have been well defined. However, based on the old and still prevalent common belief that selective inhibition of COX-2 would provide safer NSAIDs, various research groups around the world have made attempts to structurally modify classical NSAIDs as selective COX-2 inhibitors. A range of classical NSAIDs (97–116) developed in the recent past as selective COX-2 inhibitors are shown in Figure 10. Aiming to impart COX-2 selectivity, Kalgutkar and co-workers synthesized ester and amide derivatives of clinically used drug indomethacin.180 A higher alkyl homolog, octyl derivative 97 showed the highest activity against COX-2 and it was 1800-fold more selective toward COX-2 than COX-1. Tertiary amide derivatives of indomethacin were less potent inhibitors of COX-2 compared with the corresponding primary and secondary amides. Substitution of 4-chlorobenzoyl group with 4-bromobenzyl group or a hydrogen yielded inactive analogs. Similarly, replacing the 2-methyl group on the indole moiety with hydrogen also produced inactive compounds. Similar to previous approach to attain the COX-2 selectivity, Woods and co-workers replaced the carboxyl function of indomethacin with an array of thiazoles.181 In the in vitro anti-inflammatory study, derivative 98 bearing 4-bromophenyl ring appeared as the extremely potent inhibitor of COX-2 with IC50 of 0.0003 μM. Continuing their research on selective COX-2 inhibitors, Kalgutkar et al. further synthesized a series of reverse ester and amide derivatives of indomethacin.182 Most of the derivatives showed IC50 values in a low nanomolar range against COX-2 with compound 99 exhibiting >1650-fold selectivity toward COX-2 than Medicinal Research Reviews DOI 10.1002/med

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Figure 10.

Classical NSAID derivatives developed as selective COX-2 inhibitors (97–116).

COX-1. Substitution of the 4-chlorobenzoyl group on the indole nitrogen with a 4-bromobenzyl moiety retained the COX-2 selectivity. These reverse ester and amide derivatives also suppressed the COX-2 activity in mouse macrophage cell line RAW264.7. Khanna et al. with the objective to improve the COX-2 selectivity and activity, synthesized glycolamide esters of indomethacin.183 Indomethacin analog 100 bearing N-morpholinyl substitution was identified as the promising anti-inflammatory agent. In a new endeavor to improve the COX-2 selectivity, Scholz and fellow workers prepared o- and m-carbaborane derivatives of indomethacin.184 When tested against COX enzymes, the o-carbaborane derivative, 2-{1-[(4-chlorophenyl) Medicinal Research Reviews DOI 10.1002/med


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carbonyl]-5-methoxy-2-methyl-1H-indol-3-yl}acetic acid 1-(1,2-dicarba-closo-dodecaboranyl) ester (101) displayed promising COX-2 inhibitory activity, while m-isomer proved to be inactive. Introduction of adamantyl substituent or alkylene spacers at the carbaborane also yielded inactive compounds. Sulindac is considered as one of the extremely potent inhibitors of the COX enzymes. To further improve the COX-2 activity and selectivity of sulindac, Romeiro and co-workers synthesized novel analogs of sulindac and to understand the binding mode of these anti-inflammatory analogs, they performed molecular docking analysis.185 In the in vivo anti-inflammatory test, analogs 102, 103, and 104 surfaced as the potent compounds with 104 being the most active, while in the in vivo analgesic assay, analog 103 displayed maximum analgesia. Molecular docking analysis of 104 into the active site of COX-2 showed that sulfone group interacted with His-90 and Arg-513 residues via hydrogen bondings. Additionally, Tyr-385 and Ser-530 residues of the COX-2 also formed hydrogen bonds with 104, while Val-349, Phe-518, and Leu531 residues of the protein were involved in the van der Waals contacts with 104. In an altogether different approach, to improve the COX selectivity and potency, Walters and colleagues examined the effect of double bond geometry of sulindac derivatives on COX inhibition.186 They synthesized Z-isomer of 2 -des-methyl sulindac sulfide (105) and after evaluation against COX enzymes, concluded that Z-isomer inhibits both the COXs, but showed less potency than the sulindac sulfide. In order to find out the affinity of both R and S isomers of ibuprofen toward COX enzymes, Kikuchi and co-workers prepared11 C-labeled enantiomers of ibuprofen and injected intravenously.187 They noticed that both of the enantiomers were equally accumulated in the joints of arthritic mice regardless of the expression of COXs. Ketoprofen is a more potent inhibitor of COX enzymes than its propionic acid counterpart ibuprofen. Based on the crystal structures of COX proteins, Palomer and associates performed structure-based designing of ketoprofen derivatives by employing the combination of a pharmacophore and computer 3D models, and subsequently synthesized chosen derivatives as selective COX-2 inhibitors.188 From the series of compounds tested, analog 106 bearing sulfonamide pharmacophore was identified as the lead COX inhibitor with IC50 values of 18 and 0.20 μM against COX-1 and COX-2, respectively. To further improve the COX-2 affinity and activity, Levoin and fellow workers developed acyl-CoA–ketoprofen conjugate (107) by applying the mixed anhydride method.189 Since, acyl-CoA(s) have been reported to inhibit the COX enzymes and chemically acyl-CoA(s) are activated carboxylic acids that inhibit the COX by means of acylation. Therefore, it was assumed meaningful to synthesize conjugate of ketoprofen with acyl-CoA. Diastereoisomers of synthesized compound 107, that is, 107a and 107b were obtained in the optically pure form by preparative high performance liquid chromatography. Results of biological screening assay concluded that both diastereomers were reversible inhibitors of COX-1, while inhibited COX-2 irreversibly. In search of COX-2-selective ketoprofen analogs, Zarghi and fellow worker reported the synthesis and biological evaluation of ketoprofen conjugates with substituted quinoline-4-carboxylic acid.190 All the test compounds were highly potent and selective inhibitors of COX-2 with IC50 values ranging between 0.057 and 0.085 μM, while their COX-2 selectivity indices ranged between 115 and >1298.7. Compounds bearing azido pharmacophore (108 and 109) displayed potency superior to reference celecoxib. Virtual screening studies further revealed that the azido substituent was inserted deeply into the secondary pocket of the COX-2 active site and interacted with Arg-513. Flurbiprofen is indicated for the treatment of pain and inflammation, specifically associated with arthritis and ankylosing spondylitis. Bayly et al. carried out structure-based design of flurbiprofen analogs and subsequently synthesized for COX-2-selective activity.191 The analog 110 bearing diethoxy substitutions showed the foremost COX inhibitory activity with COX-2 selectivity index of 78. An attempt was made by Gupta and co-workers to improve the kinetic profile of flurbiprofen as a COX inhibitor.192 They observed that conversion of a carboxylate Medicinal Research Reviews DOI 10.1002/med

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moiety of flurbiprofen to an ester or amide abolished the slow tight-binding behavior of the drug. Loxoprofen is a propionic acid derivative and nonselective COX inhibitor. It is a prodrug, which on oral administration gets converted into an active metabolite, that is, transalcohol form. Synthesis and anti-inflammatory screening of loxoprofen analogs was reported by Yamakawa and fellow workers.193 Loxoprofen analogs with variation at the 2- or 3-location of the phenyl ring by means of p-substituted aryl group were prepared by applying Suzuki– Miyaura cross-coupling reaction between aryl bromide derivatives and a number of other boronic acids available in the market. Among the compounds screened, 2-{4 -hydroxy-5-[(2oxocyclopentyl)methyl]biphenyl-2-yl}propanoate (111) was found to be a selective inhibitor of COX-2 with a selectivity index of 31 and potency equal to that of loxoprofen. The compound 111 also displayed less gastric side effects in comparison to the parent drug. Continuing their study on loxoprofen analogs, Yamakawa et al. further synthesized and studied anti-inflammatory effects of 2-fluoroloxoprofen derivatives.194 Among them, derivative 2-[4-(cyclopentylamino)2-fluorophenyl]propanoic acid (112) exhibited higher anti-inflammatory activity and an equivalent ulcerogenic effect, compared to 2-fluoroloxoprofen. Molecular docking analysis of 112 predicted that the cyclopentanone ring was critical for COX activity. Meclofenamic acid is a drug of choice in muscular pain, arthritis, and dysmenorrhea. Kalgutkar et al. reported amide analogs of meclofenamic acid as selective COX-2 inhibitors.195 Among the analogs screened, 113 and 114 exhibited the highest COX inhibitory potential with COX-2 selectivity indices of 1.3 and 440, respectively. With the help of molecular docking analysis, authors further concluded that the requirement of Arg-120 inhibition by acid-containing NSAIDs for COX inhibitory activity must be taken with care, as in their study, selective inhibition of COX-2 caused by meclofenamic acid derivatives was Tyr-355 dependent. Nimesulide or N-(4-nitro-2-phenoxyphenyl)methanesulfonamide is a nonacidic NSAID and relatively COX2-selective inhibitor, indicated for acute inflammatory and analgesic conditions, postoperative pain, dysmenorrhoea, and arthritis. Julémont et al. reported the synthesis of pyridinic sulfonamide analogs of nimesulide.196 The alkanesulfonamide derivatives of nimesulide displayed higher selectivity ratio toward COX-2 than their trifluoromethanesulfonamide counterparts. The compound 115 was found to be an exceedingly potent inhibitor of COX-2 with activity superior than celecoxib. Furthermore, in the carrageenan-induced rat paw edema assay, compound 115 outclassed the nimesulide and demonstrated the activity greater than it. Continuing their work on nimesulide analogs, the same research team further reported the design and synthesis of another pyridinic derivative of nimesulide.197 Synthesized derivative 116 displayed the paramount activity against human COX-2. Molecular docking analysis disclosed that the presence of bromine atom in 116 imparted COX-2 selectivity, whereas substitution of bromine with chlorine reversed the action.

2. COXIBS (Selective COX-2 Inhibitors) and Their Derivatives The COX-2-selective inhibitor celecoxib was synthesized by Searle pharmaceuticals in 1997 and was approved by FDA in December 1998. Since then, several COX-2-selective inhibitors (117–129) (Fig. 11) were rapidly developed in the different labs across the world in a hope to attain GI safety of NSAIDs, which eventually proved to be a futile. Celecoxib bears the sulfonamide pharmacophore, which is responsible for the suppression of inducible COX-2 isoform. In the course of development of celecoxib analogs, Singh et al. synthesized celecoxib derivatives in which polar substitutions were introduced in the benzenesulfonamide ring of celecoxib to yield a powerful 1,5-diarylpyrazole series of COX-2 inhibitors.198 Substitution of hydroxymethyl group adjoining to the sulfonamide was found to be a principal modification that provided derivatives with COX-2-selective activity. Derivative 117, which possessed 4-(methylthio)phenyl substitution on pyrazole moiety along with polar substitution on another Medicinal Research Reviews DOI 10.1002/med


Figure 11.

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Selective inhibitors of COX-2 (COXIBS) (117–129) and COX-1 (130–133).

phenyl ring surfaced as the most potent derivative with improved COX-2 selectivity. In the subsequent study, Szabo´ and associates synthesized 1,5-diarylpyrazoles analogs of celecoxib that possessed substituted benzenesulfonamide moiety.199 Among the analogs tested, (±)-2-[4(5-ptolyl-3-trifluoromethyl-pyrazole-1-yl)-benzenesulfonylaminooxy]-propionic acid (118) and its disodium salt (118a) displayed in vivo anti-inflammatory activity superior to that of celecoxib. At the same time, compounds 118 and 118a also displayed stomach ulcerogenicity poorer than celecoxib. Rofecoxib is another selective COX-2 inhibitor, which was approved by FDA in May 1999 and marketed by Merck & Co., Inc. Nicoll-Griffith and co-workers synthesized or biosynthetically obtained oxidation, glucuronidation, reduction, and hydrolytic ring opening metabolites of rofecoxib and screened them in a whole blood assay for anti-inflammatory characters.200 They found that none of human metabolites of rofecoxib neither inhibited COX-1 nor showed any significant activity against COX-2. Intending to inhibit COX-2 by acetylation Medicinal Research Reviews DOI 10.1002/med

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of the hydroxyl group of Ser-530, Rahim et al. developed a category of isomers bearing 2-, 3-, or 4-acetoxy group at the 3-phenyl substituent of rofecoxib.201 Results of in vitro COX inhibition assay revealed that the acetoxy analogs of rofecoxib displayed remarkable COX-2 selectivity. Compound 119 with 4-acetoxy group exhibited COX-2 selectivity index of >79,365, while rofecoxib and celecoxib showed COX-2 selectivity indices of >1168 and 404, respectively. To increase the potency of refecoxib, Zarghi and colleagues synthesized methanesulfonamide derivatives of rofecoxib, wherein methylsulfonyl (SO2 Me) group was replaced with methanesulfonamido (MeSO2 NH) group, while p-position of the C-3 phenyl ring was substituted with H, F, Cl, Br, Me, and OMe groups.202 Compounds bearing electron withdrawing substituents (F, Cl, Br) at the p-position of the C-3 phenyl ring suppressed the activity of both COX-1 and COX-2, while compounds possessing electron-releasing substituents (Me or OMe) at the p-position of the C-3 phenyl ring were found to be selective inhibitors of COX-2. The compound 120 displayed highest affinity toward COX-2 with selectivity index >111. To develop the parenteral NSAID as a selective COX-2 inhibitor, Navidpour and associates synthesized water soluble tetrazolide derivative of rofecoxib.203 Replacement of the SO2 Me group of rofecoxib with tetrazole ring provided compound 121. In the in vitro COX assay, 121 exhibited remarkable inhibitory potential against the COX-2 protein. Talley et al. discovered potent and selective COX-2 inhibitor 4-[5-methyl-3-phenylisoxazol4-yl]-benzenesulfonamide or valdecoxib.204 It was developed by Searle pharmaceuticals and was approved by FDA in November 2001. In the in vitro COX assay, valdecoxib (122) exhibited IC50s of 140 and 0.005 μM against COX-1 and COX-2, respectively. It displayed ED50 values of 0.05, 0.032, and 10.2 mg/kg in the in vivo rat air pouch, rat adjuvant arthritis, and rat carrageenan edema assays, respectively. Taken together, valdecoxib was found to be an exceptionally potent inhibitor of COX-2 and until 2005, it was being prescribed in the treatment of arthritis and pain in the United States. Following the discovery of valdecoxib, for the parenteral delivery of selective COX-2 inhibitors, Talley et al. further discovered a water-soluble prodrug of valdecoxib, parecoxib sodium (123).205 In the chronic rat adjuvant arthritis model, 123 showed ED50 of 0.08 mg/kg, while in the acute carrageenan air pouch assay, it displayed 98% inhibition of inflammation at 0.3 mg/kg dose. In the carrageenan foot pad edema assay, it produced a complete blockade of carrageenan-induced hyperalgesia within 1 hr of intravenous administration and displayed ED50 of 5 mg/kg. Consequently, parecoxib sodium was considered as the outstanding NSAID of acute pain with efficacy comparable to that of potent analgesic ketorolac. Currently it is being used in many countries of the Europe, whereas it was banned in the United States in 2005, possibly due to the cardiovascular-associated adverse effects. On the flip side of the parenteral mode of administration to achieve GI safety, various studies have suggested that parenterally administered NSAIDs, which completely avoids contact of the drug with the stomach and duodenal lining, cause significant ulcer formation at rates similar to the orally administered NSAIDs.206–208 This can be possible because NSAIDs that are excreted in bile may reflux into the stomach and then cause damage to the epithelium.33 However, aspirin, which is not excreted in bile209 when administered intravenously in cats also caused GI ulcers,210 supporting the notion that nontopical actions of NSAIDs lead to an ulcer formation.33 Similar results have been observed with the enteric-coated NSAIDs.211, 212 Nunno and co-workers developed a new series of 3,4-diarylisoxazole analogs of valdecoxib, selectively targeting COX-2.213 Synthesized derivatives were assessed in the in vitro COX assay. The lead compound 124 showed IC50 comparable to that of valdecoxib against COX-2. The SAR study found that the sulfonamide group was essential for COX-2 affinity and the removal of it reversed the COX-2 selectivity. Chen et al. discovered selective COX-2 inhibitor 4-(4methane-sulfonyl-phenyl)-1-propyl-3-p-tolyl-1,5-dihydropyrrol-2-one and named it imrecoxib (125).214 In the in vitro COX assay it displayed IC50s of 0.115 and 0.018 μM against COX-1 Medicinal Research Reviews DOI 10.1002/med


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and COX-2, respectively. At the same time, IC50 of rofecoxib against COX-2 was found to be 0.0047 μM. In the carrageenan-induced paw edema assay, at 5 mg/kg dose, 125 displayed edema inhibition of 17.3%, while at the equal dose, rofecoxib demonstrated edema inhibition of 21.7%. Feng and associates further synthesized major metabolites (126 and 127) of imrecoxib and evaluated their anti-inflammatory potencies.215 The results of biological screening assay indicated that both the synthesized metabolites were potent inhibitors of COX enzymes and showed modest COX-2 selectivity, while their in vivo anti-inflammatory potencies were similar or rather superior to imrecoxib and celecoxib. Etoricoxib or 5-chloro-2-(6-methylpyridin-3-yl)-3-(4-methylsulfonylphenyl)pyridine (128) is a selective COX-2 inhibitor, developed by Merck & Co., Inc.216 It is currently marketed in many countries of the world, but not in the United States. Etoricoxib has IC50 values of 1.1 μM against COX-2 and 116 μM against COX-1 with COX-1/COX-2 selectivity index of 106. Lumiracoxib, an analog of diclofenac is a selective COX-2 inhibitor that was developed and marketed by Novartis. It binds to the COX-2 protein at a site different than the binding site of other selective COX-2 inhibitors. Although lumiracoxib has the highest in vitro COX-2 selectivity among NSAIDs, it has been withdrawn from the market in most of the countries, primarily because of hepatotoxicity associated with the treatment of osteoarthritis. To explore the effect of isosteric substitution on balancing COX-2 inhibition and TXA2 prostanoid (TP) receptor antagonism, Bertinaria et al. prepared a series of lumiracoxib derivatives via a coppercatalyzed coupling method.217 TP receptor antagonism was measured on human platelets, while COX-2 inhibition was evaluated on human isolated monocytes and human whole blood. TPα receptor binding of the most potent derivatives was assessed through radioligand binding assays. A few of the isosteric substitutions at the carboxylic acid function provided derivatives with increased TP receptor antagonism and among them, a tetrazole derivative 129 retained good COX-2 inhibitory activity and selectivity. IC50s of 129 against COX-2 in isolated monocytes and whole blood were found to be comparable to those of lumiracoxib. Furthermore, derivative 129 displayed IC50 of 12.8 μM against TXA2 and Ki value of 61 μM against TPα. The parent compound lumiracoxib showed IC50 and Ki values of 21.3 and 73.5 μM against TXA2 and TPα, respectively. Taken together, the discovery of lumiracoxib analog 129 bearing tetrazole ring acting as a balanced dual-acting agent might add to the rational design of a novel category of cardioprotective anti-inflammatory drugs.

3. Selective COX-1 Inhibitors Selective inhibition of COX-2 has been widely studied, but comparatively a small number of COX-1-selective inhibitors have also been described.218 Recent studies indicate the possible involvement of COX-1 in analgesia, neuroinflammation, and carcinogenesis.218, 219 Since COX1 is primarily localized in microglia, it is believed that its high selective inhibition rather than COX-2 is more likely to decrease neuroinflammation. In many reports, selective inhibition of COX-1 has been regarded as a promising therapeutic strategy in the prevention and treatment of neuroinflammatory diseases.218–220 Based on aforesaid accounts, Liedtke and associates designed, synthesized, and evaluated a series of (E)-2 -des-methyl-sulindac sulfide (E-DMSS) analogs as COX-1 inhibitors.218 Among them, arylmethylidene derivative of the E-DMSS (130) and sulfonamide derivatives of EDMSS (131) (Fig. 11) at 4 μM doses inhibited 75% and 99% activity of COX-1 and 1% and 15% activity of COX-2, respectively. The derivative 131 displayed IC50 of 0.47 μM against COX-1, while in same conditions parent compound sulindac sulfide showed IC50 of 0.115 μM. The SAR study showed that increasing the size and hydrophobicity of the aryl group from methylsulfanylbenzylidene to biphenylmethylidene radically increased the activity and selectivity of COX-1 inhibition. Substitutions on the biphenyl ring (e.g., fluoro, trifluoromethyl) Medicinal Research Reviews DOI 10.1002/med

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Figure 12.

NSAID derivatives developed as inhibitors of LOX and COX/LOX (134–142).

were unproductive. An attempt to augment hydrophilicity by substituting nitrogen into any of the biphenyl ring reduced the potency, which was further weakened by the introduction of multiple nitrogens in one ring. Combining the biphenyl (fluorine) retained the activity against COX-1, but at the same time increased the potency against COX-2. Introduction of an alkyl group at the α-position to the carboxyl function decreased the activity in all efforts. Derivatization of the carboxylic acid into an ester or amide analog drastically decreased activity, though substitution of sulfonimide isostere in place of the carboxylate produced the most potent and selective COX-1 inhibitor. Introduction of methyl to substituted aryl on the sulfonyl sulfur was well tolerated. Substitution of a 5 -methoxy in place of 5 -fluoro produced the most unexpected outcome with drastically decreased activity. Taken together, the E-DMSS derivatives are potent and selective COX-1 inhibitors. Calvello et al. identified valdecoxib derivatives 132 and 133 as the selective inhibitors of COX-1 (Fig. 11).219 Both the derivatives downregulated COX-1 expression without affecting COX-2 level and also suppressed NF-κB activation by inhibiting IκBα phosphorylation. The derivatives 132 and 133 displayed IC50 values of 0.09 and 0.5 μM against COX-1, while showing COX-2/COX-1 selectivity indices of 28 and >200, respectively.213, 219 4. Dual COX/LOX and LOX Inhibitors LTs play a crucial role in inflammation complementary to prostaglandins.221 They are metabolized in the arachidonic acid pathway by the lipoxygenase (LOX) enzymes.222 Numerous studies suggested that LTs, chiefly cysteinyl LTs add to GI damage by inducing microvascular injury and promoting a breakdown of the mucosal barrier.221, 223 The inhibition of COX enzymes is often related to increased level of LTs due to the deviation of arachidonic acid metabolism toward LT pathway.221, 222 Thus, few of the NSAID researchers assumed that agents inhibiting both COX and LOX by acting on the two major arachidonic acid metabolic pathways would possess a broad range of anti-inflammatory activity.122 Second, they thought that dual inhibiting agents would be almost free from stomach toxicity, which is one of the most undesirable side effects of COX inhibitors.224 The lead LOX-inhibiting NSAID derivatives (134–142) reported in various studies are presented in Figure 12. Medicinal Research Reviews DOI 10.1002/med


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Aiming for 5-LOX selective inhibitors, Kolasa et al. synthesized ibuprofen, naproxen, and indomethacin congeners of N-hydroxyurea.225 Substitution of the carboxylic group of NSAIDs with N-hydroxyurea resulted in compounds with 5-LOX selectivity. Indomethacin– N-hydroxyurea congener (134) was found to be the most selective inhibitor of 5-LOX followed by naproxen and ibuprofen congeners. Conversely, NSAIDs–N-hydroxyurea congeners were either inactive or very less active against COX-2. Aspiring to target COX and LOX, Chowdhury and co-workers also adopted dual-inhibition strategy and synthesized regioisomers of salicylic acid and N-acetyl-2-carboxy benzenesulfonamide possessing N-difluoromethyl-1,2dihydropyrid-2-one pharmacophore as the dual inhibitors of COX and 5-LOX.226 Substitution of the 2,4-difluorophenyl moiety with N-difluoromethyl-1,2-dihydropyrid-2-one in diflunisal yielded derivatives with dual selective inhibition ability of COX-2 and 5-LOX. The results indicated that C-5 N-acetyl-2-carboxybenzenesulfonamide regioisomer (135) was 1.3 and 2.8 times more potent than ibuprofen and aspirin, respectively, in the carrageenan-induced rat paw edema assay. The authors concluded that the N-difluoromethyl-1,2-dihydropyridin-2-one moiety provides a new platform for the discovery of novel dual inhibitors of COX-2 and 5-LOX. Continuing with their approach to achieve simultaneous inhibition of both COX and LOX by administering a single chemical entity, Chowdhury and associates prepared celecoxib analogs bearing N-hydroxypyrid-2(1H)one moiety along with either SO2 CH3 or SO2 NH2 group.227 Among the compounds evaluated, 136 and 137 were moderately active against COX enzymes, while against 5-LOX, 136 and 137 displayed much improved activity with IC50 values of 0.39 and 4.90 μM, respectively. Compounds 136 and 137 also displayed promising anti-inflammatory activity in the carrageenan-induced rat paw edema assay. Based on the obtained results, it can be stated that N-hydroxypyridin-2(1H)one is an convincing pharmacophore for selective 5-LOX inhibitors. In a further development of celecoxib as dual inhibitors, Chowdhury and co-workers synthesized celecoxib derivatives possessing N-difluoromethyl-1,2-dihydropyrid-2-one scaffold.228 Replacement of the tolyl ring of celecoxib by the N-difluoromethyl-1,2-dihydropyrid-2-one moiety provided compounds with dual selective inhibition capability of both COX-2 and 5-LOX. The compound, 1-(4-aminosulfonylphenyl)-5-[4-(1-difluoromethyl-1,2-dihydropyrid-2-one)]-3trifluoromethyl-1H-pyrazole (138) was found to be a potent inhibitor of COX and 5-LOX. In the carrageenan-induced rat paw edema assay, 138 displayed activity equipotent to celecoxib and superior than ibuprofen. Presence of sulfonamide pharmacophore in the analogs conveyed anti-inflammatory action stronger than that of methylsulfonyl pharmacophore. Findings indicated that the N-difluoromethyl-1,2-dihydropyridin-2-one moiety can be considered as a novel scaffold of choice for the dual inhibition of both COX-2 and 5-LOX. In an approach similar to previously discussed, the oxime derivatives of rofecoxib were synthesized by Chen and colleagues as the dual inhibitors of COX and LOX.229 In the in vitro assays, derivatives 139 and 140 were proved to be potent inhibitors of COX and LOX enzymes. Additionally, in the in vivo anti-inflammatory assay, 139 and 140 exhibited activity superior to that of 5LOX inhibitor caffeic acid and 15-LOX inhibitor nordihydroguaiaretic acid, though showed activity inferior to the selective COX-2 inhibitor celecoxib. The SAR study concluded that the introduction of p-oxime moiety at the C-3 phenyl ring of rofecoxib offers a promising scaffold for the dual inhibition of COX and LOX. Recently, Elkady et al. synthesized mPGES-1 and 5-LOX inhibitors by modifying the structure of NSAIDs by replacing the carboxylic acid functionality with sulfonamide moieties.230 The most active mPGES-1 inhibitor was lonazolac derivative (3-{4-[(4-chlorophenyl)ethynyl] phenyl}-1-phenyl-1H-pyrazol-4-yl)acetic acid (141) (IC50 : 0.16 μM), while the highest 5-LOX inhibition was achieved by indomethacin derivative [1-(4-chlorobenzyl)-2-methyl-5-(phenyl ethynyl)-1H-indol-3-yl]acetic acid (142) (IC50 : 0.9 μM).


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5. Limitations of COX and LOX Inhibitors The existence of COX-2 isoform was confirmed in 1991.231 Thereafter, it was thought that it is expressed at high levels in inflammatory sites,232 while its level in healthy tissues remains low.33 Pharmaceutical companies and various research groups around the globe were driven by the perception that selective inhibition of COX-2 would inhibit inflammatory PG synthesis while sparing gastric PG synthesis to produce the reduced GI toxicity. Although the initial enthusiasm for selective COX-2 inhibitors was faded away soon, once the more lights were shed on the distinct roles of COX-1 and COX-2 in the protection of GI mucosa. Although many studies have exhibited reduced GI toxicity of selective COX-2 inhibitors than classical NSAIDs,233–235 however, they do cause significant GI injury.14 Moreover, their cardiovascular and renal adverse effects were comparable or even higher than the conventional NSAIDs236, 237 and these factors led to the withdrawal of selective COX-2 inhibitors from the market. An elevated COX-2 levels have been observed on exposure of mucosa to an irritant,238 ischemic injury,239 and COX-1 suppression.240 This upregulation of COX-2 is protective in nature, aimed to strengthen mucosal defense by increasing mucosal blood flow and inhibiting leukocyte adherence to the vascular endothelial cells.33 The inhibition of COX-2 in any of the aforementioned conditions (irritant, ischemia, and COX-1 suppression) leads to the GI damage.33 For example, if an aspirin is coadministered with selective COX-2 inhibitors at antithrombotic doses, the benefit of selective COX-2 inhibitors over classical NSAIDs in terms of upper GI ulceration and bleeding is lost and it produces extensive injury.241 Aspirin inhibits the COX-1 greater than COX-2 and its administration induces increased synthesis of COX-2derived PGs.33 However, if it is administered together with selective COX-2 inhibitors, increased COX-2-derived PGs synthesis mechanism is suppressed, leading to a decreased mucosal resistance against injury.33 In part, gastric bleeding on coadministration of aspirin with selective COX-2 inhibitors is also caused by the ability of aspirin to inhibit the platelet aggregation.15 The fact that COX-2-derived endogenous PGs contributes significantly to ulcer healing and both the COX-1 and COX-2 play a central role in the protection of gastric mucosa was further ascertained by a study in COX-2-deficient mice, which showed increased susceptibility to damage compared with control group and developed erosions on administration of NSAIDs.242 Moreover, COX-2-deficient mice also displayed an impaired resolution of inflammation, indicating that COX-2 is a vital source of anti-inflammatory mediators.243 In summary, development of selective COX-2 inhibitors was based on the perception that inhibition of COX1 produces GI toxicity and this remains a common belief till date, despite strong evidence to the contrary33 and many papers, particularly in synthetic medicinal chemistry are still being published highlighting the development of selective COX-2 inhibitors as safer NSAIDs. Like COX-2, COX-1 also plays a key role in the protection of GI mucosa33 and therefore, the development of selective COX-1 inhibitors also suffers from limitations. For example, COX-1 inhibits gastric acid secretion,26, 27, 244 whereas it stimulates mucus30 and bicarbonate secretions,245 maintains a juxtamucosal pH gradient32 and hydrophobicity of the mucosal surface,246 decrease epithelial permeability to acid,34 and contributes to basal mucosal blood flow.35, 37 The inhibition of COX-1 also releases a potent vasoconstrictor substance endothelin-1.38 Thus, the development of selective COX-1 inhibitors for neuroinflammatory diseases appears to be an unpromising approach in the quest of safer NSAIDs. As we have discussed in the previous section that both the COX-1- and COX-2-derived PGs play a central role in the protection of GI mucosa. In this regard, inhibition of COX-1 causes a rapid compensatory rise in COX-2 level, and suppression of both enzymes leads to exacerbation of tissue injury.240, 247 For example, selective COX-2 inhibitors produce reduced upper GI toxicity than nonselective COX inhibitors in part as they do not inhibit platelet aggregation.15, 33 However, if antithrombotic dose of aspirin, which has more COX-1 inhibitory Medicinal Research Reviews DOI 10.1002/med


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potential than COX-2 is coadministered with selective COX-2 inhibitors, benefits of selective COX-2 inhibitors in terms of upper GI toxicity are lost and produce extensive hemorrhagic erosions in the stomach.15, 33 This enhanced toxicity on coadministration of NSAIDs inhibiting both COX-1 and COX-2 enzymes in part, is due to the ability of aspirin to suppress platelet aggregation.15, 33 However, in another interesting reason, aspirin irreversibly acetylates COX-1 and COX2 to inhibit the conversion of arachidonic acid to PGH2 . Although acetylated COX-2 still remains able to metabolize arachidonic acid to 15(R)-hydroxyepitetraenoic acid. The 15(R)hydroxyepitetraenoic acid is then converted into 15(R)-epi-lipoxin A4 by 5-LOX enzyme.15, 33 15(R)-epi-lipoxin A4 and its epimer lipoxin A4 (LXA4 ) are potent gastroprotective antiinflammatory substances241, 248 that inhibit neutrophil adherence to the vascular endothelial cells.42, 249 Hence, when COX-2 inhibitors are coadministered with aspirin, synthesis of 15(R)hydroxyepitetraenoic acid from arachidonic acid is blocked, ultimately leading to suppression of gastroprotective 15(R)-epi-lipoxin A4 .15, 33 This results in increased gastric damage than that observed with aspirin or selective COX-2 inhibitors alone.241, 250, 251 The gastroprotective activity of lipoxins is mediated via the FPRL-1 (formyl peptide receptor like 1) receptor.252 Additionally, it is well documented that sequential transformation of polyunsaturated fatty acids by different LOXs produces LTA4 via arachidonic acid.253 LXA4 is then generated in platelets by the oxidase activity of LOXs.253 These mediators and their stable analogs inhibit inflammation254, 255 and COX-2 plays an important role in lipoxin formation.253 Taken together, these studies indicate that dual inhibition of COX-1/COX-2 or COX/LOX would reduce the GI protection while exacerbating GI injury than the inhibitors suppressing the activity of COX or LOX alone. Thus, the dual COX/LOX inhibiting NSAIDs hold a little significance in the development of safer NSAIDs. I. Miscellaneous NSAID Derivatives Other than the synthesis of specific classes of NSAIDs, viz. NO- and H2 S-releasing NSAIDs, phospholipase-associated and phospho-NSAIDs, mPGES-1 inhibitors, COXIBS, hybrids of NSAIDs with antioxidants, anticholinergics, AChEIs, amino acids, and carbohydrates, numerous other approaches have also been explored in the discovery and development of safer NSAIDs. The agents developed through such miscellaneous approaches/strategies are shown in Figure 13 (143–161) and Figure 14 (162–171). Naproxen etemesil, a naproxen prodrug (LTNS001) (143) developed by Logical Therapeutics, Inc., is one of the most studied prodrugs, which has completed phase II clinical trials.256 It was developed to improve GI tolerability and reduce the risk of gastric ulcers in patients requiring chronic treatments of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. In a multicenter, randomized, double-blind, doubledummy trial, naproxen etemesil 1200 mg twice daily (n = 61) was compared with naproxen 500 mg twice daily (n = 59) for 7.5 days in healthy subjects of 45–70 years of age. On day 7, naproxen etemesil-treated group displayed gastroduodenal Lanza score of 2.8 ± 1.7 compared with a Lanza score of 3.5 ± 2.0 shown by naproxen (P = 0.03). Only 3.3% of naproxen etemesiltreated subjects developed gastric ulcer compared with the 15.8% of subjects developing gastric ulcers in naproxen-treated group.257 Although this study did not address the some crucial issues existing in safer NSAID development paradigm, as the systemic administration of NSAIDs also produces GI toxicity and moreover, this study does not explain the small intestine safety, which currently has limited options to deal with. In the hunt for new and potent anti-inflammatory and analgesic agents, Fahmy et al. synthesized various derivatives of O-substituted salicylamide.258 From the series of compounds screened for biological activity, derivative 144 with sulfonamide pharmacophore appeared as the highly potent anti-inflammatory and analgesic agent. In the course of development Medicinal Research Reviews DOI 10.1002/med

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Figure 13.

Miscellaneous NSAID derivatives of different classes (143–161).

of amine/amide derivatives of salicylic acid, Abdel-Alim et al. synthesized prodrugs of 5aminosalicylic acid derivatives with the nicotinamide.259 From the set of compounds evaluated, compound 145 bearing N-methylamide substitution surfaced as the lead analgesic and antiinflammatory prodrug. Branching of spacer chain with a methyl group in 145 increased the potency, which was in agreement with the fact that the presence of α-CH3 in profens increases the activity. In search of potent derivatives targeting P-selectin in arthritis, Kaila and Medicinal Research Reviews DOI 10.1002/med


Figure 14.

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Various NSAID derivatives of diverse classes (162–171).

associates synthesized analogs of quinoline salicylic acids.260 The C-8 substituted analogs were found to be superior inhibitors of P-selectin and among them, analog 146 that possessed C8-phenyl ring appeared as the most potent inhibitor of inflammation. Moser et al. designed and synthesized anti-inflammatory analogs of diclofenac and studied their quantitative SAR (QSAR).261 Compound 147 bearing o-fluoro-substituted diclofenac scaffold was found to be the most potent anti-inflammatory agent. Halogen or alkyl substituents at the o-positions of the anilino ring were most optimal for imparting anti-inflammatory activity and the compounds with no or one o-substituent were found less active. Incorporation of hydroxyl groups in addition to the two o-substituents resulted in decreased activity. QSAR studies disclosed that lipophilicity and angle of twist between the two phenyl rings were critical parameters for imparting activity. In a different approach, Bhandari et al. synthesized Schiff bases of diclofenac possessing potent anti-inflammatory and analgesic properties.262 The Schiff base, (E)-2-(2-(2,6dichlorophenylamino)phenyl)-N -(4-bromo benzylidene)acetohydrazide (148) appeared as the most potent analgesic and anti-inflammatory agent. The compound 148 also displayed less stomach lesions compared with the parent drug. In an attempt to alleviate the GI adverse effects associated with the use of indomethacin, Bandgar et al. designed and synthesized indomethacin prodrugs, which were proved to be less ulcerogenic than the parent drug.263 A prodrug of indomethacin with pivaloyloxymethyl ester (149) was equipotent to indomethacin Medicinal Research Reviews DOI 10.1002/med

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and it was found to be stable in the simulated gastric fluid, while hydrolyzed readily in the rat plasma to release the promoieties. Arisawa and co-workers designed and synthesized conformationally restricted analogs and regioisomers of indomethacin.264 Screening of the anti-inflammatory effects of these compounds on COX, P-glycoprotein (P-gp), and multidrug resistance proteins pointed out that NSAIDs-induced modulation of multidrug-resistant P-gp and multidrug-resistant protein-1 is not related to COX-1 and COX-2 inhibitory actions. The analog, 1-(4-chlorobenzoyl)-6methoxy-2-methylindole-3-yl-acetic acid (150) displayed P-gp inhibitory activity threefold superior to that of indomethacin. The SAR study disclosed that the introduction of a substituent at the 7-position of the indole nucleus abolished its COX-suppressing actions, and a substituent bulkier than the methyl group at the 2- or 6-position of indole appreciably decreased its COXinhibitory effects. Investigating to improve the analgesic action of ibuprofen, Cocco and aides synthesized amide prodrugs of ibuprofen with heteroaromatic amines and evaluated them for in vivo analgesic potency, employing acetic acid induced writhing assay in rats.265 Some of the newly synthesized derivatives showed analgesic potency similar to or superior than ibuprofen with gastrosparing characters and the compound 151 with 6-methyl-pyridin-2-yl substitution displayed the highest inhibition of acetic acid induced writhing. In a divergent approach, Khan et al. synthesized and evaluated glyceride prodrugs of ibuprofen for anti-inflammatory activity.266 Synthesized congeners were chemically stable in the acidic pH of the stomach, while hydrolyzed readily in the rat plasma to release the promoieties. The ibuprofen–distearyl glyceride conjugate 152 showed highest edema and writhing inhibitions. The gastric safety profiles of synthesized prodrugs were also found to be better than that of ibuprofen. Aspiring to circumvent the NSAIDs-related gastrotoxicity, Chatterjee et al. prepared ethylenediamine and benzathine conjugates of ibuprofen.267 Among them, ester congeners 153 and 154 demonstrated analgesia superior than ibuprofen. The conjugates 153 and 154 were also proved to be strong inhibitors of inflammation and displayed ulcerogenicity less than the parent drug. In a unique attempt, Sujith et al. synthesized Mannich bases of ibuprofen.268 In the in vivo anti-inflammatory assay, Mannich base 155 displayed edema inhibition superior to that of ibuprofen and diclofenac, while in the in vivo analgesic screening, compound 155 along with 156 displayed the maximum activity. Based on the aforementioned findings, it can be stated that Mannich bases bearing morpholino ring (155 and 156) were found to possess significant anti-inflammatory and analgesic properties. In search of potent anti-inflammatory agents, Barsoum and associates prepared ester derivatives of NSAIDs bearing phenylcarbamoylmethyl moiety.269 Among them, (4-chlorophenylcarbamoyl) methyl–ibuprofen prodrug (157) demonstrated remarkable in vivo anti-inflammatory activity. Furthermore, in the rat air pouch PGE2 inhibitory assay, level of PGE2 in the animals treated with 157 was found to be only 50.83 pg/mL, while in the indomethacin-treated group, mean concentration of PGE2 detected was 98.33 pg/mL. Thus, 157 demonstrated PGE2 inhibitory potential twofold greater than the reference indomethacin. A team led by M. Amir reported the synthesis of 6-substituted-1,2,4-triazolo[3,4-b]-1,3,4thiadiazole derivatives of naproxen.270 Among them, analog 158 demonstrated the highest analgesic and anti-inflammatory activity with weak ulcerogenic potential. Continuing with the trend of masking the carboxyl function of NSAIDs in the form of ester to reduce stomach toxicity and improve pharmacological profile, Kumar and colleagues described the synthesis of ester prodrugs of naproxen.271 From the series of naproxen ester congeners tested, prodrug 159 bearing dimethoxy substitution showed moderate anti-inflammatory and analgesic potency, while rest of the prodrugs displayed feeble activity. Recently, in a distinct approach, Wei et al. synthesized three enzymatically cleavable dendritic scaffolds of naproxen conjugates (naproxen molecules were conjugated with each other via ester or amide bonds) by applying convergent strategy.272 On a single enzymatic cleavage, these self-immolative dendritic naproxen prodrugs Medicinal Research Reviews DOI 10.1002/med


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were programmed to liberate manifold molecules of naproxen. When studied in vitro in the 50% human plasma, dendritic naproxen congener T3 (10 molecules of naproxen were conjugated with each other via ester and amide bonds) released 47.3% of the drug after 24 hr. These dendritic scaffolds did not show any significant cytotoxicity against HEK293 cells and were found to be less ulcerogenic than their monomeric (single molecule of naproxen) analog, that is, naproxen. This novel strategy signifies the importance of dendritic molecules in a prodrug-based drug-delivery systems. Fenamic acid or 2-(phenylamino)benzoic acid is an anti-inflammatory compound and NSAIDs, namely mefenamic acid, meclofenamic acid, tolfenamic acid, and flufenamic acid are structural derivatives of fenamic acid. Anthranilic acid serves as a parent structure for mefenamic acid and is regarded as less potent than mefenamic acid. Sharma et al. prepared Nsubstituted anthranilic acid analogs for anti-inflammatory screening.273 Moieties, such as pyrazoline, oxadiazole, and thiadiazole have already been reported for imparting anti-inflammatory properties, therefore, investigators synthesized anthranilic acid analogs possessing either pyrazoline and oxadiazole, or pyrazoline and thiadiazole moieties as a common scaffold to augment the potency of compounds. From the series of compounds tested, analog 160 appeared as the most potent anti-inflammatory agent that showed highest inhibition of edema. The SAR study revealed that the presence of p-methoxyphenyl ring on pyrazol moiety potentiates the anti-inflammatory activity. Recently, 2-pyridyl and 2-benzothiazol bearing mefenamic acid derivatives were synthesized in the lab of A. Razzak.274 In an egg-white induced rat paw edema assay of inflammation, synthesized derivative 161 with pyridin-2yl substitution demonstrated anti-inflammatory efficacy equal to that of the reference aspirin. Apart from synthesizing derivatives of a particular NSAID or class, a range of NSAID derivatives (162–171) (Fig. 14) of diverse classes have also been synthesized and compared for their pharmacological potencies. To overcome the limitations of traditional NSAIDs, F. A. Omar synthesized NSAID (aspirin, ibuprofen, naproxen, and indomethacin) esters of N-hydroxymethylphthalimide.275 All the prodrugs were rapidly hydrolyzed in 80% rabbit plasma and showed ulcerogenicity less than the parent compounds, examined under scanning electron microscope. In a similar study, Mahfouz and fellow workers prepared prodrugs of aspirin, ibuprofen, naproxen, and indomethacin by employing N-hydroxymethylsuccinimide and Nhydroxymethylisatin as the promoieties.276 Kinetic hydrolysis studies of these prodrugs in simulated gastric fluid of pH 2, 80% human plasma, and 10% rat liver homogenate demonstrated that these prodrugs were chemically stable, while hydrolyzed rapidly in human plasma and rat liver homogenate to liberate the parent moieties. In vivo ulcerogenic capability evaluation of prodrugs using scanning electron microscopy on stomach specimens of rats treated with oral doses of prodrugs disclosed that the synthesized ester prodrugs were less ulcerogenic than the parent drugs. An attempt of augmenting the potency of NSAIDs in a dermal delivery system via improving their topical permeability was made by Mendes and co-workers.277 To attain this, authors synthesized aminocarbonyloxymethyl prodrugs of naproxen, flufenamic acid, and diclofenac and examined for steady-state skin fluxes. Unfortunately, screened prodrugs demonstrated lower fluxes than the parent NSAIDs. This can be attributed to decreased aqueous solubility and increased partition coefficient of the synthesized prodrugs. The authors stated that log P-value of 2–3 was optimum for the maximum fluxes of NSAIDs. Elevated levels of plasminogen activators (PAs), including urokinase PA has been cited decisive in the pathogenesis of rheumatoid arthritis. Yang and fellow workers assessed the efficacy of NSAIDs (diclofenac, nimesulide, celecoxib, valdecoxib, rofecoxib, and etoricoxib) on the regulation of urokinase PA and inhibitor, and gelatinases in the early-stage osteoarthritic knee of humans.278 The study concluded that NSAIDs suppressed the PA/plasmin system and gelatinases expression in osteoarthritis and thereby influenced the progression of the disease. For a site-specific delivery of NSAIDs to the inflamed joints, Yadav et al. developed quaternary Medicinal Research Reviews DOI 10.1002/med

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ammonium salts of tropinol esters of NSAIDs (indomethacin, ketoprofen, biphenylacetic acid, flurbiprofen, ibuprofen, 6-MNA, and naproxen).279 The quaternized ester derivatives were radiolabeled with 99m Technetium (99m Tc) and their specific accumulation in the inflamed tissues was detected employing scintigraphy. Most of the quaternized esters exhibited anti-inflammatory potency similar to their parent drugs, tested in Freund’s adjuvant arthritis model. Naproxen derivative 162 reduced paw edema volume with the highest degree. Results of c-imaging studies indicated that quaternary esters were selectively localized in the inflamed tissues. Li et al. screened the effects of indomethacin, celecoxib, and dexamethasone on the regulation of Akt, FOXO (Forkhead box O), and p27Kip1 and studied the correlation of these factors with the propagation of human osteoblasts (hOBs).280 Earlier reports found that NSAIDs mediated upregulation of p27Kip1 plays a vital role in the NSAIDs-triggered cell cycle arrest of hOBs. The Akt has been accounted for the arrest of p27Kip1 promoter action via FOXO in various types of cells. Results indicated that NSAIDs (indomethacin, celecoxib, and dexamethasone) inhibited the phosphorylated Akt in hOBs, while promoted the levels of FOXO and p27Kip1 . Recently, Cai and aides synthesized a series of bone targeting rheine–NSAID (aspirin, ibuprofen, naproxen, diclofenac, and indomethacin) prodrugs bearing anthraquinone moiety.281 These compounds showed remarkable ability of binding with the hydroxyl apatite and also exhibited significant anti-inflammatory activity with improved gastric safety profile. In the xylene-induced mice auricle tumefaction model of acute anti-inflammatory activity, diclofenac prodrug 163 appeared as the lead candidate, which demonstrated the highest inhibition of auricle tumefaction. For incorporating muscle relaxation activity along with anti-inflammatory properties, Abdel-Azeem and co-workers prepared novel chlorzoxazone prodrugs of ibuprofen, naproxen, and diclofenac.282 Study revealed that the chlorzoxazone–ibuprofen prodrug (164) demonstrated the highest muscle relaxant activity with improved gastric tolerability, whereas chlorzoxazone–naproxen prodrug (165) emerged as the most active anti-inflammatory agent. In a routine study, Verma et al. synthesized NSAID (salicylic acid, ketoprofen, aceclofenac, flurbiprofen, mefenamic acid, and indomethacin) conjugates with 5-phenyl-2-aminothiazole for antiphlogistic activities.283 In vivo analgesic activity evaluated by emplyong acetic acid induced writhing and hot plate stimulation assays in mice disclosed that the indomethacin analog 166 displayed the maximum potency with noteworthy inhibition of writhing and thermal stimulus. Moreover, compound 166 inhibited edema to a greater extent than the reference indomethacin. At the same time, synthesized prodrugs were also proved to be less ulcerogenic than the parent compounds. In a study similar to the previous one, Uluda˘g and fellow workers synthesized ester and amide prodrugs of ibuprofen, ketoprofen, and mefenamic acid.284 From the series of compounds screened, 4-tert-butylphenyl substituted ketoprofen ester (167) emerged as the lead prodrug that demonstrated utmost edema inhibition and analgesia. In a different study, to decrease the gastric toxicity by concealing the free acidic group of NSAIDs, Mahdi et al. prepared ester conjugates of NSAIDs (ibuprofen, naproxen, and mefenamic acid) with gabapentin, using glycol as a spacer.285 Results of hydrolysis study indicated that these compounds were chemically stable in the acidic pH and this observable fact improved the gastric safety profile of the synthesized prodrugs. On the contrary, prodrugs were hydrolyzed at a reasonably higher rate in the human plasma to liberate the promoieties. After 2 hr exposure to human plasma, naproxen prodrug 168 showed 88% metabolic transformation with t1/2 of 37.6 min. Sticking with the previous approach, Mahdi et al. synthesized novel mutual prodrugs of NSAIDs with sulfa drugs (sulfathiazole and sulfadiazine), employing glycolic acid as a spacer.286 To improve the stomach tolerability, a free carboxylic group of NSAIDs was masked in the form of ester. Synthesized prodrugs were chemically stable in the acidic pH, while hydrolyzed at a significantly higher rate in the human plasma. After 4 hr exposure to 80% human plasma, naproxen prodrug 169 displayed 87.23% of metabolic hydrolysis. Continuing their efforts in search of potent and safer NSAIDs, Mahdi et al. further synthesized a Medicinal Research Reviews DOI 10.1002/med


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new series of NSAID (naproxen, indomethacine, diclofenac and mefanamic acid) derivatives bearing 4-(methylsulfonyl)aniline pharmacophore.287 From the set of compounds evaluated in the egg-white induced rat paw edema assay, naproxen–4-methylsulfonylanilne conjugate (170) displayed the highest potency with activity greater than the clinically used drug diclofenac. Recently, Gund and co-workers synthesized nicotinic acid conjugates of various NSAIDs, namely naproxen, diclofenac, indomethacin, sulindac, ibuprofen, and aspirin.288 These conjugates were evaluated against TNF-α and IL-6 cytokines by using the immunosorbent assay. Among them, diclofenac conjugate 171 was found to be potential inhibitor of inflammatory mediators and it showed 44% and 48% inhibition of TNF-α and IL-6, respectively. At the same time, diclofenac displayed 35% and 42% suppression of TNF-α and IL-6, correspondingly.

3. LIMITATIONS OF NSAID PRODRUGS Developments of NSAID prodrugs are based on the premise that if these drugs can pass through the stomach in the intact form, then they are supposed not to inhibit the PG synthesis in the stomach and thereby not to be ulcerogenic.104 This concept is somewhere similar to the enteric-coated NSAIDs, which have been failed to overcome the gastric ulceration and bleeding associated with the NSAIDs.211, 289 Systemic inhibition of COX is accountable for the alleviation of pain and inflammation, has also been associated with the gastroduodenal toxicity.104 An injectable ketorolac after 4 days of treatment produced the gastric ulcers in 77year-old woman.206 Once the prodrug is absorbed and metabolized to release the active parent moiety, it would produce pharmacological actions same as that of the parent drug.104 NSAIDs, which are excreted in bile may reflux back into the stomach to cause the toxicity.33 Second, prodrug approach is completely based on to spare the upper GI tract toxicity, while ignoring the safety profile in the small intestine.104 NSAIDs that undergo enterohepatic circulation are more prone to cause enteropathy. Chronic treatment of sulindac and nabumatone prodrugs in at-risk patients has been failed to provide upper GI tract safety.290–292 Clinical studies of prodrugs largely include acute gastric and gastroduodenal toxicity evaluations257 and as a result, often producing the data inclined toward favorable profile of prodrugs.104 Thus, the prodrug approach neither addresses GI damage caused by systemic inhibition of COX activity, after it is absorbed and metabolized to liberate the parent drug, nor it addresses the small intestine injury caused by excretion of its toxic metabolites in the bile.104, 293

4. COMBINATION OF NSAIDs WITH PPIs AND H2 RAs: ENTEROPATHY STILL PERSISTS The combination of NSAIDs with gastric acid secretion inhibitors (PPIs or H2 RAs) is one of the current treatment options against NSAID-induced gastropathy.15 One such drug, Vimovo (naproxen + esomeprazole) was recently launched by AstraZeneca.15 Another combination of aspirin and esomeprazole as brand name Axanum has been approved in European Union member states and Norway. The pathogenesis of NSAID enteropathy is different from that of NSAID gastropathy.15 Presently, there is no particular treatment approved for NSAID-induced enteropathy. However, the advent of video capsule endoscopy and doubleballoon enteroscopy has made it possible to assess the small intestine damage caused by NSAIDs and other coadministered agents. Studies have found that in a population at low risk for NSAID gastroenteropathy, coadministration of PPI with the NSAID caused a high incidence (55–75%) of small intestine damage.294–297 In fact, recent studies have revealed that PPIs actually exacerbate NSAID-induced enteropathy instead of providing beneficial effects.15 Medicinal Research Reviews DOI 10.1002/med

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Chronic treatment with PPIs or H2 RAs causes a disproportionate increase in microbial population capable of deconjugating bile acids or converts primary bile acids to secondary bile acids.107, 298–300 The latter is particularly more damaging to intestinal epithelial cells and produces ulcers.104, 301 Moreover, deconjugation of bile acids increases bile acid hydrophobicity, which in turn increases the ability of bile acid to disrupt the cellular membrane of enterocytes.302 Wallace et al. demonstrated that concurrent treatment of PPIs (omeprazole or lansoprazole) with NSAIDs (naproxen or celecoxib) in rats produces considerably higher intestinal ulceration and bleeding than the control group treated with vehicle plus the NSAID.303 The authors observed that PPI did not change the plasma and biliary levels of NSAID, but changes in intestinal flora were observed with a substantial increase in gram-negative bacteria in the small intestine and a significant decrease in the population of Actinobacteria.15, 303 This dysbiosis effect increases the susceptibility of small intestine to injury. The chronic administration of PPIs has also been associated with serious side effects, such as interference with antiplatelet treatments, malabsorption of certain vitamins and nutrients, and increased risk of bone fracture.15, 304 In summary, combination and/or coadministration of NSAIDs with PPIs or H2 RAs can reduce the incidence of NSAID-induced gastropathy but is not able to prevent the NSAID-induced enteropathy. This indicates little use of gastric acid secretion inhibition in the NSAID-induced enteropathy.

5. BINDING MODE OF NSAIDs TO COX PROTEINS Various molecular modeling and docking studies have established the binding mode of NSAIDs with COX-1 and COX-2. One of the oldest NSAID aspirin acetylates Ser-530 residue of the COX, while mutant S530A is resistant to aspirin acetylation.305–307 Carboxylate function of phenylpropionic acid derivative flurbiprofen forms hydrogen bonds with Arg-120 and Tyr-355 residues of the COX-1, whereas another analog ibuprofen binds with COX-1 in a fashion similar to flurbiprofen, but instead of hydrogen bonding it forms ion pairs with Arg-120 and Tyr-355 residues.305 It was found that the hydrogen/ion-pair interaction with Arg-120 is critical for the COX-1 inhibition.308 Surprisingly, a methyl ester analog of indomethacin inhibits COX-2 R120A mutant more potently than the wild-type counterpart, indicating that the interaction with Arg-120 is not significant for COX-2 inhibitory activity.305, 309 A complex of indomethacin and COX-2 demonstrated that indomethacin binds deep into the COX active site.310 The pchlorobenzoyl ring makes a contact with Leu-384, whereas the benzoyl oxygen interacts with Ser-530 residue. The carboxylate group of indomethacin remains salt bridged with Arg-120 and also interacts with Tyr-355, while indole moiety interacts with Val-349 of the COX-2.305 Diclofenac makes a complex at the active site of COX-2 in a distinct inverted binding mode, where its carboxylic acid moiety forms hydrogen bonds with Ser-530 and Tyr-385 residues.305 Contrasting to the most NSAIDs, carboxylic acid moiety of diclofenac neither makes a contact with Arg-120 nor interacts with Tyr-355.305 The phenylacetic acid scaffold remains enclosed by the side chains of Leu-352, Leu-384, Tyr-385, and Trp-387, while dichlorophenyl scaffold establishes van der Waals contacts with Val-349, Val-523, Ala-527, and Leu-531 residues of the COX-2.305 The carboxylate function of lumiracoxib, a COX-2-selective derivative of diclofenac, forms hydrogen bonds with Tyr-385 and Ser-530 in a manner identical to that of diclofenac.311 An attempt was made by Fabiola et al. to explain the selectivity of nimesulide with COX-2. They performed a molecular modeling analysis of nimesulide with COX-1 and with the mutants of COX-1, simulating COX-2. The study found that 1523V and S516A mutations contributed to the COX-2 selectivity.312 Studies based on the sequence alignments between COX-1 and COX-2 and homology modeling of human COX-2 discovered that only Val-523 residue of the COX-2 binding site is not Medicinal Research Reviews DOI 10.1002/med


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conserved in the COX-1.313, 314 Crystal structure of human COX-2 demonstrated that Val-523 (Ile in COX-1) of the active site and Val-434 and Arg-513 residues of the secondary shell (His513 and Ile-434 in COX-1) account for 25% greater active site area of the COX-2 than that of COX-1.305 Complex of celecoxib analog 4-(5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol1-yl)benzenesulfonamide (SC-558) with COX-2 disclosed that the sulfonamide pharmacophore was critical for the activity and binds with Val-523 of the COX-2.305 Computational studies of celecoxib performed by Price et al. discovered that a mutation of Ile-523 to Val-523 played a critical role in the COX-2 selectivity, whereas unfavorable steric connection between the sulfonamide oxygen and the δ-methyl group of Ile-523 weakened the binding with COX-1.315 The replacement of His-513 with Arg-513 residue was found to be insignificant.315 Sharma et al. derived a QSAR model for COX inhibitors and found that the molecular mass weighted descriptors (MATS2m, BEHm2, and MATS5m), atomic polarizabilities, and van der Waals volumes weighted descriptors (GATS6p and MATS6v) played a crucial part in the validation of COX inhibitory activity of the compounds.316

6. FUTURE SCOPE OF DEVELOPING NSAIDs A new approach to NO donation was jointly discovered by NicOx and Merck in September 2010, during the course of their joint research pact.317 Merck is currently investigating this new strategy in certain cardiovascular indications, while NicOx holds rights in other areas.317 This novel approach may be applied in the development of new classes of NO-releasing new molecular entities, intended to offer a different mechanism for controlling the release of NO while retaining the potential therapeutic benefits.317 Naproxcinod (NO–naproxen), the first agent of the CINOD class of NSAIDs, which is being developed by NicOx S.A., France for use in the osteoarthritis has completed phase III clinical trials. NicOx met with the US Food and Drug Administration (FDA) on April 3, 2012, to discuss the proposed use of naproxcinod 375 mg twice daily (bid), for the treatment of signs and symptoms of osteoarthritis of the knee, under a proposed new NDA (New Drug Application) that would require additional clinical data prior to any such NDA submission.318 On February 14, 2014, NicOx announced to refocus on naproxcinod development efforts and it granted rights to an undisclosed financial partner to enter into a period of exclusive evaluation to assess the potential development of naproxcinod.319 Moreover, on a positive note, the European commission has granted orphan drug designation for naproxcinod in October 2013 for the treatment of Duchenne muscular dystrophy.319 H2 S-releasing agent ATB-346 is another promising gaseous mediator that has shown significantly improved GI profile. On administration with low-dose aspirin or PPI for several days, it did not produce noticeable small intestine damage, and thus, seems a potential candidate against NSAID-induced gastroenteropathy.320 Moreover, ATB-346 has also demonstrated GI safety in animals with compromised mucosal defense or with preexisting ulcers, a condition in which selective COX-2 inhibitors produce significant GI bleeding and damage in humans.320 According to Antibe therapeutics webpage, phase I clinical study of ATB-346 has already been started on June 26, 2014.320 Given the current scenario in the development of safer NSAIDs, gaseous mediator releasing NSAIDs appear flag bearer against the NSAID-induced gastroenteropathy and cardiovascular adverse effects. Naproxen etemesil, a naproxen prodrug (LT-NS001) is currently being developed by Logical Therapeutics, Inc., has completed phase II clinical studies.256 It could be a better option against NSAID-induced gastropathy over coadministration of NSAIDs with PPIs and/or H2 RAs. However, little has been addressed by naproxen etemesil to overcome the Medicinal Research Reviews DOI 10.1002/med

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NSAID-induced enteropathy. Phosphatidylcholine-associated aspirin PL2200 (325 mg), developed by PLx Pharma Inc., USA, has received FDA approval for the indications of pain, fever, and cardiovascular disease.321 On coadministration with celecoxib, it has shown negligible gastric injury while maintaining the hydrophobic GI mucosal barrier.321 PLx Pharma is also developing phosphatidylcholine-associated other NSAIDs, namely PL1100 (ibuprofen), PL4100 (indomethacin), and PL5100 (diclofenac).321 These findings indicate that in near future NSAIDs can be conjugated with the phosphatidylcholine to protect the GI mucosa by maintaining surface-active hydrophobic layer of phospholipids. An approach to develop phospho-NSAIDs resembles to the idea of phosphatidylcholine-associated NSAIDs. However, they have not yet been investigated in detail. Terminal prostaglandin synthase mPGES-2 inhibitors can be devoid of cardiovascular adverse effects. However, there is possibility that inhibition of VEGF by these agents would delay the ulcer healing process.33 Antioxidant–NSAID hybrids bearing GI protective antioxidant moiety, such as TEMPO or polyphenol may also have therapeutic implications. Combination of naproxen and PPI esomeprazole (Vimovo) was developed by AstraZeneca15 and several such agents are also being developed.322 Although this approach could be a useful against NSAID-induced gastropathy but certainly is not capable to overcome the NSAID-induced enteropathy. Based on the evidence for an important role of enteric bacteria in the development of NSAID-induced enteropathy, exploration of probiotics and prebiotics has also been suggested.15 The distinct mechanism of injury in the stomach and duodenum versus the small intestine would likely to make the future development of safer NSAIDs paradigm a very challenging prospect.

7. CONCLUSION In this review, we have made an attempt to provide an overview of the recent developments in NSAID therapeutics, particularly covering medicinal chemistry aspects. For the last two decades, breakthrough findings have enabled us to better understand the origin and the development of NSAIDs-induced gastropathy and enteropathy. Discovery of selective COX-2 inhibitors offered a glimpse of hope for the anti-inflammatory medications. However, the initial enthusiasm for selective COX-2 inhibitors was faded away soon due to the emergence of GI and cardiovascular-associated adverse effects. Development of NSAIDs or conjugation of NSAIDs to the moieties that could address both NSAID-induced gastropathy and enteropathy along with the cardiovascular safety is the need of the hour. Currently there are more limited options to deal with NSAID-induced enteropathy than the NSAID-induced gastropathy. However, gaseous mediator releasing NSAIDs have shown promising small intestine and cardiovascular safety profiles. Along with them, phosphatidylicholine-associated NSAIDs, phospho-NSAIDs, antioxidant–NSAID hybrids, probiotics, and prebiotics are likely to provide new and promising therapeutic options to prevent and treat the NSAID-induced gastroenteropathy.

8. ABBREVIATIONS

AchEI asp cele COX diclo DMSS

= = = = = =

acetylcholinesterase inhibitor aspirin celecoxib cyclooxygenase diclofenac 2 -des-methyl-sulindac sulfide


RECENT DEVELOPMENTS IN CHIMERIC NSAIDs flur GI H2 RAs H2 S ibu IL IκBα imre indo keto ketorol loxo lumi LTB4 meclo mef acid mPGES-1 NF-κB nime NO npr NSAIDs PG PGE2 PPIs rofe salicyl sulin tolfen valde VEGF 4-BPA 6-MNA parecox

= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = =

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flurbiprofen gastrointestinal histamine H2 -receptor antagonists hydrogen sulfide ibuprofen interleukin nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor imrecoxib indomethacin ketoprofen ketorolac loxoprofen lumiracoxib leukotriene B4 meclofenamic acid mefenamic acid microsomal prostaglandin E2 synthase-1 nuclear factor-kappaB nimesulide nitric oxide naproxen nonsteroidal anti-inflammatory drugs prostaglandin prostaglandin E2 proton-pump inhibitors rofecoxib salicylamide sulindac tolfenamic acid valdecoxib vascular endothelial growth factor 4-biphenylacetic acid 6-methoxy-2-naphthylacetic acid parecoxib

REFERENCES 1. Musumba C, Pritchard DM, Pirmohamed M. Review article: Cellular and molecular mechanisms of NSAID-induced peptic ulcers. Aliment Pharmacol Ther 2009;30:517–531. 2. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 1999;340:1888–1899. 3. Singh G. Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med 1998;105:31S–38S. 4. Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol Suppl 1999;56:18–24. 5. Singh G. Gastrointestinal complications of prescription and over-the-counter nonsteroidal antiinflammatory drugs: A view from the ARAMIS database. Am J Ther 2000;7:115–121. 6. Lanza FL, Chan FK, Quigley EM. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol 2009;104:728–738. Medicinal Research Reviews DOI 10.1002/med

50

r SUTHAR AND SHARMA

7. Lanas A, Perez-Aisa MA, Feu F, Ponce J, Saperas E, Santolaria S, Rodrigo L, Balanzo J, Bajador E, Almela P, Navarro JM, Carballo F, Castro M, Quintero E. A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with nonsteroidal anti-inflammatory drug use. Am J Gastroenterol 2005;100:1685–1693. 8. Hla T, Neilson K. Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci USA 1992;89:7384–7388. 9. Meade EA, Smith WL, DeWitt DL. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem 1993;268:6610–6614. 10. Xie W, Robertson DL, Simmons DL. Mitogen-inducible prostaglandin G/H synthase: A new target for nonsteroidal anti-inflammatory drugs. Drug Dev Res 1992;25:249–265. 11. Cao C, Matsumura K, Watanabe Y. Induction of cyclooxygenase-2 in the brain by cytokines. Ann N Y Acad Sci 1997;813:307–309. ¨ 12. Klein T, Nusing RM, Pfeilschifter J, Ullrich V. Selective inhibition of cyclooxygenase 2. Biochem Pharmacol 1994;48:1605–1610. 13. Laine L, Connors LG, Reicin A, Hawkey CJ, Burgos-Vargas R, Schnitzer TJ. Serious lower gastrointestinal adverse clinical events with non-selective NSAID or coxib use. Gastroenterology 2003;124:288–292. 14. Lanas A, Baron JA, Sandler RS, Horgan K, Bolognese J, Oxenius B. Peptic ulcer and bleeding events associated with rofecoxib in a 3-year colorectal adenoma chemoprevention trial. Gastroenterology 2007;132:490–497. 15. Wallace JL. NSAID gastropathy and enteropathy: Distinct pathogenesis likely necessitates distinct prevention strategies. Br J Pharmacol 2012;165:67–74. 16. Lichtenstein DR, Wolfe MM. COX-2-Selective NSAIDs: New and improved? JAMA 2000;284:1297–1299. 17. Whittle BJ. Temporal relationship between cyclooxygenase inhibition, as measured by prostacyclin biosynthesis, and the gastrointestinal damage induced by indomethacin in the rat. Gastroenterology 1981;80:94–98. 18. Rainsford KD, Willis C. Relationship of gastric mucosal damage induced in pigs by antiinflammatory drugs to their effects on prostaglandin production. Dig Dis Sci 1982;27:624–635. 19. Wallace JL, Devchand PR. Emerging roles for cyclooxygenase-2 in gastrointestinal mucosal defense. Br J Pharmacol 2005;145:275–282. 20. Reuter BK, Asfaha S, Buret A, Sharkey KA, Wallace JL. Exacerbation of inflammation-associated colonic injury in rat through inhibition of cyclooxygenase-2. J Clin Invest 1996;98:2076–2085. 21. Mizuno H, Sakamoto C, Matsuda K, Wada K, Uchida T, Noguchi H, Akamatsu T, Kasuga M. Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology 1997;112:387–397. 22. Ma L, del Soldato P, Wallace JL. Divergent effects of new cyclooxygenase inhibitors on gastric ulcer healing: Shifting the angiogenic balance. Proc Natl Acad Sci USA 2002;99:13243–13247. 23. Knapp HR, Oelz O, Sweetman BJ, Oates JA. Synthesis and metabolism of prostaglandins E2, F2α and D2 by the rat gastrointestinal tract. Stimulation by a hypertonic environment in vitro. Prostaglandins 1978;15:751–757. ¨ 24. Peskar BM, Gunter B, Peskar BA. Prostaglandins and prostaglandin metabolites in human gastric juice. Prostaglandins 1980;20:419–427. 25. Peskar BM. On the synthesis of prostaglandins by human gastric mucosa and its modification by drugs. Biochim Biophys Acta 1977;487:307–314. 26. Kato S, Aihara E, Yoshii K, Takeuchi K. Dual action of prostaglandin E2 on gastric acid secretion through different EP-receptor subtypes in the rat. Am J Physiol Gastrointest Liver Physiol 2005;289:G64–G69.



r 51

27. Nishio H, Terashima S, Nakashima M, Aihara E, Takeuchi K. Involvement of prostaglandin E receptor EP2 subtype and prostacyclin IP receptor in decreased acid response in damaged stomach. J Physiol Pharmacol 2007;58:407–421. 28. Chu S, Tanaka S, Kaunitz JD, Montrose MH. Dynamic regulation of gastric surface pH by luminal pH. J Clin Invest 1999;103:605–612. 29. Garner A, Flemstrom C, Allen A, Heylings JR, McQueen S. Gastric mucosal protective mechanisms: Roles of epithelial bicarbonate and mucus secretions. Scand J Gastroenterol 1984;101:79–86. 30. Takahashi S, Takeuchi K, Okabe S. EP4 receptor mediation of prostaglandin E2-stimulated mucus secretion by rabbit gastric epithelial cells. Biochem Pharmacol 1999;58:1997–2002. 31. Takeuchi K, Tanaka A, Kato S, Aihara E, Amagase K. Effect of (S)-4-(1-(5-chloro-2-(4fluorophenyoxy)benzamido)ethyl) benzoic acid (CJ-42794), a selective antagonist of prostaglandin E receptor subtype 4, on ulcerogenic and healing responses in rat gastrointestinal mucosa. J Pharmacol Exp Ther 2007;322:903–912. 32. Baumgartner HK, Starodub OT, Joehl JS, Tackett L, Montrose MH. Cyclooxygenase 1 is required for pH control at the mouse gastric surface. Gut 2004;53:1751–1757. 33. Wallace JL. Prostaglandins, NSAIDs, and gastric mucosal protection: Why doesn’t the stomach digest itself? Physiol Rev 2008;88:1547–1565. 34. Takezono Y, Joh T, Oshima T, Suzuki H, Seno K, Yokoyama Y, Alexander JS, Itoh M. Role of prostaglandins in maintaining gastric mucus-cell permeability against acid exposure. J Lab Clin Med 2004;143:52–58. 35. Araki H, Ukawa H, Sugawa Y, Yagi K, Suzuki K, Takeuchi K. The roles of prostaglandin E receptor subtypes in the cytoprotective action of prostaglandin E2 in rat stomach. Aliment Pharmacol Ther 2000;14(Suppl 1):116–124. 36. Kotani T, Kobata A, Nakamura E, Amagase K, Takeuchi K. Roles of cyclooxygenase-2 and prostacyclin/IP receptors in mucosal defense against ischemia/reperfusion injury in mouse stomach. J Pharmacol Exp Ther 2006;316:547–555. 37. Wallace JL, McKnight W, Reuter BK, Vergnolle N. NSAID induced gastric damage in rats: Requirement for inhibition of both cyclooxygenase 1 and 2. Gastroenterology 2000;119:706–714. 38. Funatsu T, Chono K, Hirata T, Keto Y, Kimota A, Sasamata M. Mucosal acid causes gastric mucosal microcirculatory disturbance in nonsteroidal anti-inflammatory drug-treated rats. Eur J Pharmacol 2007;554:53–59. 39. Wallace JL. Nonsteroidal anti-inflammatory drugs and gastroenteropathy: The second hundred years. Gastroenterology 1997;112:1000–1016. 40. Ajuebor MN, Singh A, Wallace JL. Cyclooxygenase-2-derived prostaglandin D2 is an early antiinflammatory signal in experimental colitis. Am J Physiol Gastrointest Liver Physiol 2000;279:G238– G244. 41. Gilroy DW, Colville-Nash PR, McMaster S, Sawatzky DA, Willoughby DA, Lawrence T. Inducible cyclooxygenase-derived 15-deoxy12–14PGJ2 brings about acute inflammatory resolution in rat pleurisy by inducing neutrophil and macrophage apoptosis. FASEB J 2003;17:2269–2271. 42. Serhan CN, Brain SD, Buckley CD, Gilroy DW, Haslett C, O’Neill LA, Perretti M, Rossi AG, Wallace JL. Resolution of inflammation: State of the art, definitions and terms. FASEB J 2007;21:325– 332. 43. Hogaboam CM, Bissonnette EY, Chin BC, Befus AD, Wallace JL. Prostaglandins inhibit inflammatory mediator release from rat mast cells. Gastroenterology 1993;104:122–129. 44. Kunkel SL, Chensue SW. Arachidonic acid metabolites regulate interleukin-1 production. Biochem Biophys Res Commun 1985;128:892–897. 45. Kunkel SL, Chensue SW, Phan SH. Prostaglandins as endogenous mediators of interleukin 1 production. J Immunol 1986;136:186–192. 46. Kunkel SL, Wiggins RC, Chensue SW, Larrick J. Regulation of macrophage tumor necrosis factor production by prostaglandin E2. Biochem Biophys Res Commun 1986;137:404–410.


52

r SUTHAR AND SHARMA

47. Ham EA, Soderman DD, Zanetti ME, Dougherty HW, McCauley E, Kuehl FA. Inhibition by prostaglandins of leukotriene B4 release from activated neutrophils. Proc Natl Acad Sci USA 1983;80:4349–4353. 48. Haurand M, Floh L. Leukotriene formation by human polymorphonuclear leukocytes from endogenous arachidonate. Physiological triggers and modulation by prostanoids. Biochem Pharmacol 1989;38:2129–2137. 49. Wertheim WA, Kunkel SL, Standiford TJ, Burdick MD, Becker FS, Wilke CA, Gilbert AR, Strieter RM. Regulation of neutrophil-derived IL-8: The role of prostaglandin E2, dexamethasone, and IL-4. J Immunol 1993;151:2166–2175. 50. Brzozowska I, Targosz A, Sliwowski Z, Kwiecien S, Drozdowicz D, Pajdo R, Konturek PC, Brzozowski T, Pawlik M, Konturek SJ, Pawlik WW, Hahn EG. Healing of chronic gastric ulcers in diabetic rats treated with native aspirin, nitric oxide (NO)-derivative of aspirin and cyclooxygenase (COX)-2 inhibitor. J Physiol Pharmacol 2004;55:773–790. 51. Ma L, Wang WP, Chow JY, Lam SK, Cho CH. The role of polyamines in gastric mucus synthesis inhibited by cigarette smoke or its extract. Gut 2000;47:170–177. 52. Miura S, Tatsuguchi A, Wada K, Takeyama H, Shinji Y, Hiratsuka T, Futagami S, Miyake K, Gudis K, Mizokami Y, Matsuoka T, Sakamoto C. Cyclooxygenase-2-regulated vascular endothelial growth factor release in gastric fibroblasts. Am J Physiol Gastrointest Liver Physiol 2004;287:G444– G451. 53. Takahashi M, Maeda S, Ogura K, Terano A, Omata M. The possible role of vascular endothelial growth factor (VEGF) in gastric ulcer healing: Effect of sofalcone on VEGF release in vitro. J Clin Gastroenterol 1998;27(Suppl 1):S178–S182. 54. Wallace JL, Dicay M, McKnight W, Dudar GK. Platelets accelerate gastric ulcer healing through presentation of vascular endothelial growth factor. Br J Pharmacol 2006;148:274–278. 55. Lechi C, Andrioli G, Gaino S, Tommasoli R, Zuliani V, Ortolani R, Degan M, Benoni G, Bellavite P, Lechi A, Minuz P. The antiplatelet effects of a new nitroderivative of acetylsalicylic acid- an in vitro study of inhibition on the early phase of platelet activation and on TXA2 production. Thromb Haemost 1996;76:791–798. 56. Lazzarato L, Donnola M, Rolando B, Marini E, Cena C, Coruzzi G, Guaita E, Morini G, Fruttero R, Gasco A, Biondi S, Ongini E. Searching for new NO-donor aspirin-like molecules: A new class of nitrooxy-acyl derivatives of salicylic acid. J Med Chem 2008;51:1894–1903. 57. Lazzarato L, Donnola M, Rolando B, Chegaev K, Marini E, Cena C, Di Stilo A, Fruttero R, Biondi S, Ongini E, Gasco A. (Nitrooxyacyloxy)methyl esters of aspirin as novel nitric oxide releasing aspirins. J Med Chem 2009;52:5058–5068. 58. Rolando B, Lazzarato L, Donnola M, Marini E, Joseph S, Morini G, Pozzoli C, Fruttero R, Gasco A. Water-soluble nitric-oxide-releasing acetylsalicylic acid (ASA) prodrugs. ChemMedChem 2013;8:1199–1209. 59. Viappiani S, Kabile F, Wallace JL, Bolla MI. The cyclooxygenase-inhibiting nitric oxide donator (CINOD) NCX 285 reduces inflammation and pain without causing serious gastrointestinal toxicity in animals (abstract). American College of Rheumatology Annual Scientific Meeting, San Francisco, CA, Vol. 1281; 2008. 60. Mizoguchi H, Hase S, Tanaka A, Takeuchi K. Lack of small intestinal ulcerogenecity of nitric oxide-releasing indomethacin, NCX-530, in rats. Aliment Pharmacol Ther 2001;15:257–267. 61. Gaitan G, Ahuir FJ, Del Soldato P, Herrero JF. Comparison of the antinociceptive activity of two new NO-releasing derivatives of the NSAID S-ketoprofen in rats. Br J Pharmacol 2004;143:533–540. 62. Bézière N, Goossens L, Pommery J, Vezin H, Touati N, Hénichart JP, Pommery N. New NSAIDsNO hybrid molecules with antiproliferative properties on human prostatic cancer cell lines. Bioorg Med Chem Lett 2008;18:4655–4657. 63. Wallace JL, Reuter B, Cicala C, McKnight W, Grisham MB, Cirino G. Novel nonsteroidal antiinflammatory drug derivatives with markedly reduced ulcerogenic properties in the rat. Gastroenterology 1994;107:173–179. Medicinal Research Reviews DOI 10.1002/med


r 53

64. Kartasasmita RE, Laufer S, Lehmann J. NO-donors (VII [1]): Synthesis and cyclooxygenase inhibitory properties of N- and S-nitrooxypivaloyl-cysteine derivatives of naproxen—A novel type of NO-NSAID. Arch Pharm (Weinheim) 2002;8:363–366. 65. Wallace JL, Viappiani S, Bolla M. Cyclooxygenase-inhibiting nitric oxide donators for osteoarthritis. Trends Pharmacol Sci 2009;30:112–117. 66. Fiorucci S, Di Lorenzo A, Renga B, Farneti S, Morelli A, Cirino G. Nitric oxide (NO)-releasing naproxen (HCT-3012 [(S)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid 4-(nitrooxy)butyl ester]) interactions with aspirin in gastric mucosa of arthritic rats reveal a role for aspirin-triggered lipoxin, prostaglandins, and NO in gastric protection. J Pharmacol Exp Ther 2004;311:1264–1271. 67. Hawkey CJ, Jones JI, Atherton CT, Skelly MM, Bebb JR, Fagerholm U, Jonzon B, Karlsson P, Bjarnason IT. Gastrointestinal safety of AZD3582, a cyclooxygenase inhibiting nitric oxide donator: Proof of concept study in humans. Gut 2003;52:1537–1542. 68. Lohmander LS, McKeith D, Svensson O, Malmenäs M, Bolin L, Kalla A, Genti G, Szechinski J, Ramos-Remus C. A randomised, placebo controlled, comparative trial of the gastrointestinal safety and efficacy of AZD3582 versus naproxen in osteoarthritis. Ann Rheum Dis 2005;64:449–456. 69. Karlsson J, Pivodic A, Aguirre D, Schnitzer TJ. Efficacy, safety, and tolerability of the cyclooxygenase-inhibiting nitric oxide donator naproxcinod in treating osteoarthritis of the hip or knee. J Rheumatol 2009;36:1290–1297. 70. White WB, Schnitzer TJ, Fleming R, Duquesroix B, Beekman M. Effects of the cyclooxygenase inhibiting nitric oxide donator naproxcinod versus naproxen on systemic blood pressure in patients with osteoarthritis. Am J Cardiol 2009;104:840–845. 71. Efficacy and safety study of naproxcinod in subjects with osteoarthritis of the hip. Available at: http://clinicaltrials.gov/ct2/show/record/NCT00541489?term=naproxcinod. 72. Efficacy and safety study of naproxcinod in subjects with osteoarthritis of the knee. Available at: http://clinicaltrials.gov/ct2/show/record/NCT00504127?term=naproxcinod. 73. Analgesic efficacy and safety study of naproxcinod in subjects with osteoarthritis of the knee. Available at: http://clinicaltrials.gov/ct2/show/record/NCT00542555?term=naproxcinod. 74. Uaesoontrachoon K, Quinn JL, Tatem KS, Van Der Meulen JH, Yu Q, Phadke A, Miller BK, Gordish-Dressman H, Ongini E, Miglietta D, Nagaraju K. Long-term treatment with naproxcinod significantly improves skeletal and cardiac disease phenotype in the mdx mouse model of dystrophy. Hum Mol Genet 2014;23:3239–3249. 75. Ellis JL, Augustyniak ME, Cochran ED, Earl RA, Garvey DS, Gordon LJ, Janero DR, Khanapure SP, Letts LG, Melim TL, Murty MG, Schwalb DJ, Shumway MJ, Selig WM, Trocha AM, Young DV, Zemtseva IS. NMI-1182, a gastro-protective cyclo-oxygenase-inhibiting nitric oxide donor. Inflammopharmacology 2005;12:521–534. 76. Ranatunge RR, Augustyniak ME, Dhawan V, Ellis JL, Garvey DS, Janero DR, Letts LG, Richardson SK, Shumway MJ, Trocha AM, Young DV, Zemtseva IS. Synthesis and anti-inflammatory activity of a series of N-substituted naproxen glycolamides: Nitric oxide-donor naproxen prodrugs. Bioorg Med Chem 2006;14:2589–2599. 77. Blackler R, Syer S, Bolla M, Ongini E, Wallace JL. Gastrointestinal-sparing effects of novel NSAIDs in rats with compromised mucosal defence. PLoS One 2012;7:e35196. 78. Ziakas GN, Rekka EA, Gavalas AM, Eleftheriou PT, Tsiakitzis KC, Kourounakis PN. Nitric oxide releasing derivatives of tolfenamic acid with anti-inflammatory activity and safe gastrointestinal profile. Bioorg Med Chem 2005;13:6485–6492. 79. Nemmani KV, Mali SV, Borhade N, Pathan AR, Karwa M, Pamidiboina V, Senthilkumar SP, Gund M, Jain AK, Mangu NK, Dubash NP, Desai DC, Sharma S, Satyam A. NO-NSAIDs: Gastric-sparing nitric oxide-releasable prodrugs of non-steroidal anti-inflammatory drugs. Bioorg Med Chem Lett 2009;19:5297–5301. 80. Borhade N, Pathan AR, Halder S, Karwa M, Dhiman M, Pamidiboina V, Gund M, Deshattiwar JJ, Mali SV, Deshmukh NJ, Senthilkumar SP, Gaikwad P, Tipparam SG, Mudgal J, Dutta MC, Burhan AU, Thakre G, Sharma A, Deshpande S, Desai DC, Dubash NP, Jain AK, Sharma S, Medicinal Research Reviews DOI 10.1002/med

54

81.

82. 83.

84.

85.

86.

87. 88.

89.

90.

91.

92.

93.

94.

95.

r SUTHAR AND SHARMA Nemmani KV, Satyam A. NO-NSAIDs. Part 3: Nitric oxide-releasing prodrugs of non-steroidal anti-inflammatory drugs. Chem Pharm Bull 2012;60:465–481. Chowdhury MA, Abdellatif KR, Dong Y, Yu G, Huang Z, Rahman M, Das D, Velázquez CA, Suresh MR, Knaus EE. Celecoxib analogs possessing a N-(4-nitrooxybutyl)piperidin-4-yl or N-(4nitrooxybutyl)-1,2,3,6-tetrahydropyridin-4-yl nitric oxide donor moiety: Synthesis, biological evaluation and nitric oxide release studies. Bioorg Med Chem Lett 2010;20:1324–1329. Engelhardt FC, Shi YJ, Cowden CJ, Conlon DA, Pipik B, Zhou G, McNamara JM, Dolling UH. Synthesis of a NO-releasing prodrug of rofecoxib. J Org Chem 2006;71:480–491. Schroeder JD, Augustyniak M, Bandarage RR, Bandarage UK, Cochran E, Earl R, Ezawa M, Fang X, Garvey DS, Gaston RD, Janero DR, Khanapure SP, Letts LG, Marek P, Martino A, Murty M, Saha J, Shumway M, Stevenson CA, Tam SW, Trocha M, Wey S-J, Young DV. NMI1093: A nitricoxide-enhanced cyclooxygenase-2-selective inhibitor with cardioprotective potential (abstract). 224th American Chemical Society National Meeting (Division of Medicinal Chemistry), Boston, MA, 2002;316. Bandarage UK, Chen L, Fang X, Garvey DS, Glavin A, Janero DR, Letts LG, Mercer GJ, Saha JK, Schroeder JD, Shumway MJ, Tam SW. Nitrosothiol esters of diclofenac: Synthesis and pharmacological characterization as gastrointestinal-sparing prodrugs. J Med Chem 2000;43:4005–4016. Cena C, Lolli ML, Lazzarato L, Guaita E, Morini G, Coruzzi G, McElroy SP, Megson IL, Fruttero R, Gasco A. Antiinflammatory, gastrosparing, and antiplatelet properties of new NO-donor esters of aspirin. J Med Chem 2003;46:747–754. Lazzarato L, Cena C, Rolando B, Marini E, Lolli ML, Guglielmo S, Guaita E, Morini G, Coruzzi G, Fruttero R, Gasco A. Searching for new NO-donor aspirin-like molecules: Furoxanylacyl derivatives of salicylic acid and related furazans. Bioorg Med Chem 2011;19:5852–5860. Lolli ML, Cena C, Medana C, Lazzarato L, Morini G, Coruzzi G, Manarini S, Fruttero R, Gasco A. A new class of ibuprofen derivatives with reduced gastrotoxicity. J Med Chem 2001;44:3463–3468. ´ de Carvalho PS, Marostica M, Gambero A, Pedrazzoli J Jr. Synthesis and pharmacological characterization of a novel nitric oxide-releasing diclofenac derivative containing a benzofuroxan moiety. Eur J Med Chem 2010;45:2489–2493. Velázquez C, Praveen Rao PN, Knaus EE. Novel nonsteroidal antiinflammatory drugs possessing a nitric oxide donor diazen-1-ium-1,2-diolate moiety: Design, synthesis, biological evaluation, and nitric oxide release studies. J Med Chem 2005;48:4061–4067. Velázquez CA, Chen QH, Citro ML, Keefer LK, Knaus EE. Second-generation aspirin and indomethacin prodrugs possessing an O2-(acetoxymethyl)-1-(2-carboxypyrrolidin-1-yl)diazenium1,2-diolate nitric oxide donor moiety: Design, synthesis, biological evaluation, and nitric oxide release studies. J Med Chem 2008;51:1954–1961. Abdellatif KR, Chowdhury MA, Dong Y, Das D, Yu G, Velázquez CA, Suresh MR, Knaus EE. Dinitroglyceryl and diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of aspirin, indomethacin and ibuprofen: Synthesis, biological evaluation and nitric oxide release studies. Bioorg Med Chem Lett 2009;19:3014–3018. Abdellatif KR, Chowdhury MA, Velázquez CA, Huang Z, Dong Y, Das D, Yu G, Suresh MR, Knaus EE. Celecoxib prodrugs possessing a diazen-1-ium-1,2-diolate nitric oxide donor moiety: Synthesis, biological evaluation and nitric oxide release studies. Bioorg Med Chem Lett 2010;20:4544– 4549. Jain S, Tran S, El Gendy MA, Kashfi K, Jurasz P, Velázquez-Mart´ınez CA. Nitric oxide release is not required to decrease the ulcerogenic profile of nonsteroidal anti-inflammatory drugs. J Med Chem 2012;55:688–696. Paolocci N, Jackson MI, Lopez BE, Miranda K, Tocchetti CG, Wink DA, Hobbs AJ, Fukuto JM. The pharmacology of nitroxyl (HNO) and its therapeutic potential: Not just the Janus face of NO. Pharmacol Ther 2007;113:442–458. Fukuto JM, Cisneros CJ, Kinkade RL. A comparison of the chemistry associated with the biological signaling and actions of nitroxyl (HNO) and nitric oxide (NO). J Inorg Biochem 2013;118:201–208.



r 55

96. Fukuto JM, Hobbs AJ, Ignarro LJ. Conversion of nitroxyl (HNO) to nitric oxide (NO) in biological systems: The role of physiological oxidants and relevance to the biological activity of HNO. Biochem Biophys Res Commun 1993;196:707–713. 97. Helm L, Merbach AE. Inorganic and bioinorganic solvent exchange mechanisms. Chem Rev 2005;105:1923–1959. 98. Eldik RV, Ivanovic-Burmacovic I. Advances in inorganic chemistry. In: Doctorovich F, Bikiel DE, Pellegrino J, Suárez SA, Matr´ı MA, Eds. Azarone (HNO) Interaction with Hemeproteins and Metalloporphyrins, Vol. 64. San Diego: Academic Press; 2012. p 97–139. 99. Basudhar D, Bharadwaj G, Cheng RY, Jain S, Shi S, Heinecke JL, Holland RJ, Ridnour LA, Caceres VM, Spadari-Bratfisch RC, Paolocci N, Velázquez-Mart´ınez CA, Wink DA, Miranda KM. Synthesis and chemical and biological comparison of nitroxyl- and nitric oxide-releasing diazeniumdiolate-based aspirin derivatives. J Med Chem 2013;56:7804–7820. 100. Huang Z, Velázquez CA, Abdellatif KR, Chowdhury MA, Reisz JA, DuMond JF, King SB, Knaus EE. Ethanesulfohydroxamic acid ester prodrugs of nonsteroidal anti-inflammatory drugs (NSAIDs): Synthesis, nitric oxide and nitroxyl release, cyclooxygenase inhibition, anti-inflammatory, and ulcerogenicity index studies. J Med Chem 2011;54:1356–1364. 101. Schnitzer TJ, Hochberg MC, Marrero CE, Duquesroix B, Frayssinet H, Beekman M. Efficacy and safety of naproxcinod in patients with osteoarthritis of the knee: A 53-week prospective randomized multicenter study. Semin Arthritis Rheum 2011;40:285–297. 102. Baerwald C, Verdecchia P, Duquesroix B, Frayssinet H, Ferreira T. Efficacy, safety, and effects on blood pressure of naproxcinod 750 mg twice daily compared with placebo and naproxen 500 mg twice daily in patients with osteoarthritis of the hip: A randomized, double-blind, parallel-group, multicenter study. Arthritis Rheum 2010;62:3635–3644. 103. Schnitzer TJ, Kivitz A, Frayssinet H, Duquesroix B. Efficacy and safety of naproxcinod in the treatment of patients with osteoarthritis of the knee: A 13-week prospective, randomized, multicenter study. Osteoarthritis Cartilage 2010;18:629–639. 104. Wallace JL. Mechanisms, prevention and clinical implications of nonsteroidal anti-inflammatory drug-enteropathy. World J Gastroenterol 2013;19:1861–1876. 105. Wallace JL, Caliendo G, Santagada V, Cirino G, Fiorucci S. Gastrointestinal safety and antiinflammatory effects of a hydrogen sulfide-releasing diclofenac derivative in the rat. Gastroenterology 2007;132:261–271. 106. Wallace JL, Caliendo G, Santagada V, Cirino G. Markedly reduced toxicity of a hydrogen sulphidereleasing derivative of naproxen (ATB-346). Br J Pharmacol 2010;159:1236–1246. 107. Blackler RW, Gemici B, Manko A, Wallace JL. NSAID-gastroenteropathy: New aspects of pathogenesis and prevention. Curr Opin Pharmacol 2014;19:11–16. 108. Wallace JL, Syer S, Denou E, de Palma G, Vong L, McKnight W, Jury J, Bolla M, Bercik P, Collins SM, Verdu E, Ongini E. Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis. Gastroenterology 2011;141:1314–1322. 109. Lazzarato L, Chegaev K, Marini E, Rolando B, Borretto E, Guglielmo S, Joseph S, Di Stilo A, Fruttero R, Gasco A. New nitric oxide or hydrogen sulfide releasing aspirins. J Med Chem 2011;54:5478–5484. 110. Kodela R, Chattopadhyay M, Kashfi K. NOSH-aspirin: A novel nitric oxide–hydrogen sulfidereleasing hybrid: A new class of anti-inflammatory pharmaceuticals. ACS Med Chem Lett 2012;3:257–262. 111. Kodela R, Chattopadhyay M, Kashfi K. Synthesis and biological activity of NOSH-naproxen (AVT219) and NOSH-sulindac (AVT-18A) as potent anti-inflammatory agents with chemotherapeutic potential. Med Chem Commun 2013;4:1472–1481. 112. Chan MV, Wallace JL. Hydrogen sulfide-based therapeutics and gastrointestinal diseases: Translating physiology to treatments. Am J Physiol Gastrointest Liver Physiol 2013;305:G467–G473. 113. Flores-Santana W, Moody T, Chen W, Gorczynski MJ, Shoman ME, Velázquez C, Thetford A, Mitchell JB, Cherukuri MK, King SB, Wink DA. Nitroxide derivatives of non-steroidal antiMedicinal Research Reviews DOI 10.1002/med

56

114. 115. 116. 117. 118. 119. 120.

121. 122. 123. 124. 125.

126.

127.

128.

129. 130.

131.

132. 133.

r SUTHAR AND SHARMA inflammatory drugs exert anti-inflammatory and superoxide dismutase scavenging properties in A459 cells. Br J Pharmacol 2012;165:1058–1067. Nakao A, Sugimoto R, Billiar TR, McCurry KR. Therapeutic antioxidant medical gas. J Clin Biochem Nutr 2009;44:1–13. Samuni A, Krishna CM, Mitchell JB, Collins CR, Russo A. Superoxide reaction with nitroxides. Free Radic Res Commun 1990;9:241–249. Samuni A, Mitchell JB, DeGraff W, Krishna CM, Samuni U, Russo A. Nitroxide SOD-mimics: Modes of action. Free Radic Res Commun 1991;12–13(Pt 1):187–194. Soule BP, Hyodo F, Matsumoto K, Simone NL, Cook JA, Krishna MC, Mitchell JB. The chemistry and biology of nitroxide compounds. Free Radic Biol Med 2007;42:1632–1650. Samuni AM, DeGraff W, Krishna MC, Mitchell JB. Cellular sites of H2O2-induced damage and their protection by nitroxides. Biochim Biophys Acta 2001;1525:70–76. Manon B, Sharma PD. Design, synthesis and evaluation of diclofenac-antioxidant mutual prodrugs as safer NSAIDs. Indian J Chem 2009;48B:1279–1287. Madhukar M, Sawraj S, Sharma PD. Design, synthesis and evaluation of mutual prodrug of 4biphenylacetic acid and quercetin tetramethyl ether (BPA−QTME) as gastrosparing NSAID. Eur J Med Chem 2010;45:2591–2596. Sawraj S, Bhardawaj TR, Sharma PD. Design, synthesis and evaluation of novel indomethacinflavonoid mutual prodrugs as safer NSAIDs. Med Chem Res 2011;20:687–694. Redasani VK, Bari SB. Synthesis and evaluation of mutual prodrugs of ibuprofen with menthol, thymol and eugenol. Eur J Med Chem 2012;56:134–138. Chandiran S, Vyas S, Sharma N, Sharma M. Synthesis and evaluation of antioxidant-S-(+)ibuprofen hybrids as gastro sparing NSAIDs. Med Chem 2013;9:1006–1016. Lim YJ, Dial EJ, Lichtenberger LM. Advent of novel phosphatidylcholine-associated nonsteroidal anti-inflammatory drugs with improved gastrointestinal safety. Gut Liver 2013;7:7–15. Lichtenberger LM, Wang ZM, Romero JJ, Ulloa C, Perez JC, Giraud MN, Barreto JC. Nonsteroidal anti-inflammatory drugs (NSAIDs) associate with zwitterionic phospholipids: Insight into the mechanism and reversal of NSAID-induced gastrointestinal injury. Nat Med 1995;1:154–158. Giraud MN, Motta C, Romero JJ, Bommelaer G, Lichtenberger LM. Interaction of indomethacin and naproxen with gastric surface-active phospholipids: A possible mechanism for the gastric toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs). Biochem Pharmacol 1999;57:247–254. Lichtenberger LM, Zhou Y, Jayaraman V, Doyen JR, O’Neil RG, Dial EJ, Volk DE, Gorenstein DG, Boggara MB, Krishnamoorti R. Insight into NSAID-induced membrane alterations, pathogenesis and therapeutics: Characterization of interaction of NSAIDs with phosphatidylcholine. Biochim Biophys Acta 2012;1821:994–1002. Lichtenberger LM, Zhou Y, Dial EJ, Raphael RM. NSAID injury to the gastrointestinal tract: Evidence that NSAIDs interact with phospholipids to weaken the hydrophobic surface barrier and induce the formation of unstable pores in membranes. J Pharm Pharmacol 2006;58:1421–1428. Zhou Y, Plowman SJ, Lichtenberger LM, Hancock JF. The anti-inflammatory drug indomethacin alters nanoclustering in synthetic and cell plasma membranes. J Biol Chem 2010;285:35188–35195. Zhou Y, Hancock JF, Lichtenberger LM. The nonsteroidal anti-inflammatory drug indomethacin induces heterogeneity in lipid membranes: Potential implication for its diverse biological action. PLoS One 2010;5:e8811. Cryer B, Bhatt DL, Lanza FL, Dong JF, Lichtenberger LM, Marathi UK. Low-dose aspirininduced ulceration is attenuated by aspirin-phosphatidylcholine: A randomized clinical trial. Am J Gastroenterol 2011;106:272–277. Anand BS, Romero JJ, Sanduja SK, Lichtenberger LM. Phospholipid association reduces the gastric mucosal toxicity of aspirin in human subjects. Am J Gastroenterol 1999;94:1818–1822. Schmassmann A, Zoidl G, Peskar BM, Waser B, Schmassmann-Suhijar D, Gebbers JO, Reubi JC. Role of the different isoforms of cyclooxygenase and nitric oxide synthase during gastric ulcer healing



134.

135.

136. 137.

138.

139. 140.

141.

142.

143.

144.

145. 146.

147.

148. 149. 150. 151.

r 57

in cyclooxygenase-1 and -2 knockout mice. Am J Physiol Gastrointest Liver Physiol 2006;290:G747– G756. Lanza FL, Marathi UK, Anand BS, Lichtenberger LM. Clinical trial: Comparison of ibuprofenphosphatidylcholine and ibuprofen on the gastrointestinal safety and analgesic efficacy in osteoarthritic patients. Aliment Pharmacol Ther 2008;28:431–442. Kao YC, Goddard PJ, Lichtenberger LM. Morphological effects of aspirin and prostaglandin on the canine gastric mucosal surface. Analysis with a phospholipid-selective cytochemical stain. Gastroenterology 1990;98:592–606. Rahme E, Bernatsky S. NSAIDs and risk of lower gastrointestinal bleeding. Lancet 2010;376:146– 148. Mackenzie GG, Sun Y, Huang L, Xie G, Ouyang N, Gupta RC, Johnson F, Komninou D, Kopelovich L, Rigas B. Phospho-sulindac (OXT-328), a novel sulindac derivative, is safe and effective in colon cancer prevention in mice. Gastroenterology 2010;139:1320–1332. Huang L, Mackenzie G, Ouyang N, Sun Y, Xie G, Johnson F, Komninou D, Rigas B. The novel phospho-non-steroidal anti-inflammatory drugs, OXT-328, MDC-22 and MDC-917, inhibit adjuvant-induced arthritis in rats. Br J Pharmacol 2011;162:1521–1533. Xie G, Wong CC, Cheng KW, Huang L, Constantinides PP, Rigas B. In vitro and in vivo metabolic studies of phospho-aspirin (MDC-22). Pharm Res 2012;29:3292–3301. Xie G, Sun Y, Nie T, Mackenzie GG, Huang L, Kopelovich L, Komninou D, Rigas B. Phosphoibuprofen (MDC-917) is a novel agent against colon cancer: Efficacy, metabolism, and pharmacokinetics in mouse models. J Pharmacol Exp Ther 2011;337:876–886. Xie G, Nie T, Mackenzie GG, Sun Y, Huang L, Ouyang N, Alston N, Zhu C, Murray OT, Constantinides PP, Kopelovich L, Rigas B. The metabolism and pharmacokinetics of phosphosulindac (OXT-328) and the effect of difluoromethylornithine. Br J Pharmacol 2012;165:2152–2166. Xie G, Wong CC, Cheng KW, Huang L, Constantinides PP, Rigas B. Regioselective oxidation of phospho-NSAIDs by human cytochrome P450 and flavin monooxygenase isoforms: Implications for their pharmacokinetic properties and safety. Br J Pharmacol 2012;167:222–232. Mattheolabakis G, Mackenzie GG, Huang L, Ouyang N, Cheng KW, Rigas B. Topically applied phospho-sulindac hydrogel is efficacious and safe in the treatment of experimental arthritis in rats. Pharm Res 2013;30:1471–1482. Halen PK, Chagti KK, Giridhar R, Yadav MR. Synthesis and pharmacological evaluation of some dual-acting amino-alcohol ester derivatives of flurbiprofen and 2-[1,1 -biphenyl-4-yl]acetic acid: A potential approach to reduce local gastrointestinal toxicity. Chem Biodivers 2006;3:1238–1248. Halen PK, Chagti KK, Giridhar R, Yadav MR. Substituted aminoalcohol ester analogs of indomethacin with reduced toxic effects. Med Chem Res 2007;16:101–111. Halen PK, Chagti KK, Giridhar R, Yadav MR. Combining anticholinergic and anti-inflammatory activities into a single moiety: A novel approach to reduce gastrointestinal toxicity of ibuprofen and ketoprofen. Chem Biol Drug Des 2007;70:450–455. Halen PK, Raval MK, Chagti KK, Giridhar R, Yadav MR. Synthesis and evaluation of some gastrointestinal sparing anti-inflammatory aminoethyl ester derivatives of naphthalene-based NSAIDs. Arch Pharm (Weinheim) 2007;340:88–94. van Maanen MA, Vervoordeldonk MJ, Tak PP. The cholinergic anti-inflammatory pathway: Towards innovative treatment of rheumatoid arthritis. Nat Rev Rheumatol 2009;5:229–232. Tsuno N. Donepezil in the treatment of patients with Alzheimer’s disease. Expert Rev Neurother 2009;9:591–598. Guay DR. Rivastigmine transdermal patch: Role in the management of Alzheimer’s disease. Consult Pharm 2008;23:598–609. Marco L, do Carmo Carreiras M. Galanthamine, a natural product for the treatment of Alzheimer’s disease. Recent Pat CNS Drug Discov 2006;1:105–111.


58

r SUTHAR AND SHARMA

152. Brenner T, Nizri E, Irony-Tur-Sinai M, Hamra-Amitay Y, Wirguin I. Acetylcholinesterase inhibitors and cholinergic modulation in Myasthenia Gravis and neuroinflammation. J Neuroimmunol 2008;201–202:121–127. 153. Tracey KJ. The inflammatory reflex. Nature 2002;420:853–859. 154. Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 2007;117:289–296. 155. Young S, Fabio K, Guillon C, Mohanta P, Halton TA, Heck DE, Flowers RA 2nd, Laskin JD, Heindel ND. Peripheral site acetylcholinesterase inhibitors targeting both inflammation and cholinergic dysfunction. Bioorg Med Chem Lett 2010;20:2987–2990. 156. Young SC, Fabio KM, Huang MT, Saxena J, Harman MP, Guillon CD, Vetrano AM, Heck DE, Flowers RA 2nd, Heindel ND, Laskin JD. Investigation of anticholinergic and non-steroidal anti-inflammatory prodrugs which reduce chemically induced skin inflammation. J Appl Toxicol 2012;32:135–141. 157. Cohen SG, Chishti SB, Elkind JL, Reese H, Cohen JB. Effects of charge, volume, and surface on binding of inhibitor and substrate moieties to acetylcholinesterase. J Med Chem 1985;28:1309–1313. 158. Bahia MS, Katare YK, Silakari O, Vyas B, Silakari P. Inhibitors of microsomal prostaglandin E2 synthase-1 enzyme as emerging anti-inflammatory candidates. Med Res Rev 2014;34:825–855. 159. Shinji Y, Tsukui T, Tatsuguchi A, Shinoki K, Kusunoki M, Suzuki K, Hiratsuka T, Wada K, Futagami S, Miyake K, Gudis K, Sakamoto C. Induced microsomal PGE synthase-1 is involved in cyclooxygenase-2-dependent PGE2 production in gastric fibroblasts. Am J Physiol Gastrointest Liver Physiol 2005;288:G308–315. 160. Riendeau D, Aspiotis R, Ethier D, Gareau Y, Grimm EL, Guay J, Guiral S, Juteau H, Mancini JA, Méthot N, Rubin J, Friesen RW. Inhibitors of the inducible microsomal prostaglandin E2 synthase (mPGES-1) derived from MK-886. Bioorg Med Chem Lett 2005;15:3352–3355. 161. Gillard J, Ford-Hutchinson AW, Chan C, Charleson S, Denis D, Foster A, Fortin R, Leger S, McFarlane CS, Morton H, Piechuta H, Riendeau D, Rouzer CA, Rokach J, Young R, MacIntyre DE, Peterson L, Bach T, Eiermann G, Hopple S, Humes J, Hupe L, Luell S, Metzger J, Meurer R, Miller DK, Opas E, Pacholok S. L-663,536 (MK-886) (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5isopropylindol-2-yl]-2,2 – dimethylpropanoic acid), a novel, orally active leukotriene biosynthesis inhibitor. Can J Physiol Pharmacol 1989;67:456–464. 162. Ma L, Elliott SN, Cirino G, Buret A, Ignarro LJ, Wallace JL. Platelets modulate gastric ulcer healing: Role of endostatin and vascular endothelial growth factor release. Proc Natl Acad Sci USA 2001;98:6470–6475. 163. Koeberle A, Werz O. Microsomal prostaglandin E2 synthase-1. In: Levin JI, Laufer S, Eds. AntiInflammatory Drug Discovery. Cambridge: Royal Society of Chemistry; 2012. p 7–34. 164. Jia Z, Zhang A, Zhang H, Dong Z, Yang T. Deletion of microsomal prostaglandin E synthase-1 increases sensitivity to salt loading and angiotensin II infusion. Circ Res 2006;99:1243–1251. 165. Jia Z, Guo X, Zhang H, Wang MH, Dong Z, Yang T. Microsomal prostaglandin synthase-1-derived prostaglandin E2 protects against angiotensin II-induced hypertension via inhibition of oxidative stress. Hypertension 2008;52:952–959. 166. Zhang DJ, Chen LH, Zhang YH, Yang GR, Dou D, Gao YS, Zhang XY, Kong XM, Zhao P, Pu D, Wei MF, Breyer MD, Guan YF. Enhanced pressor response to acute Ang II infusion in mice lacking membrane-associated prostaglandin E2 synthase-1. Acta Pharmacol Sin 2010;31:1284–1292. 167. Jia Z, Aoyagi T, Kohan DE, Yang T. mPGES-1 deletion impairs aldosterone escape and enhances sodium appetite. Am J Physiol Renal Physiol 2010;299:F155–F166. 168. Jia Z, Aoyagi T, Yang T. mPGES-1 protects against DOCA-salt hypertension via inhibition of oxidative stress or stimulation of NO/cGMP. Hypertension 2010;55:539–546. 169. Degousee N, Fazel S, Angoulvant D, Stefanski E, Pawelzik SC, Korotkova M, Arab S, Liu P, Lindsay TF, Zhuo S, Butany J, Li RK, Audoly L, Schmidt R, Angioni C, Geisslinger G, Jakobsson PJ, Rubin BB. Microsomal prostaglandin E2 synthase-1 deletion leads to adverse left ventricular remodeling after myocardial infarction. Circulation 2008;117:1701–1710. Medicinal Research Reviews DOI 10.1002/med


r 59

170. Shalaby AM, Abo-Ghalia AM, el-Araky WI, Awad HM. Synthesis and comparative anti-phlogistic potency of new proteinogenic amino acid conjugates of 2-[2,6-dichlorophenyl-1-amino]phenyl acetic acid “diclofenac.” Acta Pol Pharm 1998;55:211–221. 171. Abo-Ghalia MH, Shalaby AM, el-Eraqi WI, Awad HM. Synthesis and anti-phlogistic potency of some new non-proteinogenic amino acid conjugates of “Diclofenac.” Amino Acids 1999;16:425– 440. 172. Mishra A, Veerasamy R, Jain PK, Dixit VK, Agrawal RK. Synthesis, characterization and pharmacological evaluation of amide prodrugs of ketorolac. Eur J Med Chem 2008;43:2464–2472. 173. Curcio A, Sasso O, Melisi D, Nieddu M, La Rana G, Russo R, Gavini E, Boatto G, Abignente E, Calignano A, Rimoli MG. Galactosyl prodrug of ketorolac: Synthesis, stability, and pharmacological and pharmacokinetic evaluations. J Med Chem 2009;52:3794–3800. 174. Zhang YC, Li YX, Guan HS. Synthesis of indomethacin conjugates with D-glucosamine. Chin Chem Lett 2005;16:179–182. 175. Zhao X, Tao X, Wei D, Song Q. Pharmacological activity and hydrolysis behavior of novel ibuprofen glucopyranoside conjugates. Eur J Med Chem 2006;41:1352–1358. 176. Mishra A, Veerasamy R, Jain PK, Dixit VK, Agrawal RK. Synthesis, characterization and pharmacological evaluation of amide prodrugs of flurbiprofen. J Braz Chem Soc 2008;19:89–100. 177. Rasheed A, Kumar CK A. Synthesis, hydrolysis and pharmacodynamic profiles of novel prodrugs of mefenamic acid. Int J Curr Pharm Res 2009;1:47–55. 178. Galanakis D, Kourounakis AP, Tsiakitzis KC, Doulgkeris C, Rekka EA, Gavalas A, Kravaritou C, Charitos C, Kourounakis PN. Synthesis and pharmacological evaluation of amide conjugates of NSAIDs with L-cysteine ethyl ester, combining potent antiinflammatory and antioxidant properties with significantly reduced gastrointestinal toxicity. Bioorg Med Chem Lett 2004;14:3639–3643. 179. Li J, Kuang Y, Shi J, Gao Y, Zhou J, Xu B. The conjugation of nonsteroidal anti-inflammatory drugs (NSAID) to small peptides for generating multifunctional supramolecular nanofibers/hydrogels. Beilstein J Org Chem 2013;9:908–917. 180. Kalgutkar AS, Marnett AB, Crews BC, Remmel RP, Marnett LJ, Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors. J Med Chem 2000;43:2860–2870. 181. Woods KW, McCroskey RW, Michaelides MR, Wada CK, Hulkower KI, Bell RL. Thiazole analogues of the NSAID indomethacin as selective COX-2 inhibitors. Bioorg Med Chem Lett 2001;11:1325–1328. 182. Kalgutkar AS, Crews BC, Saleh S, Prudhomme D, Marnett LJ. Indolyl esters and amides related to indomethacin are selective COX-2 inhibitors. Bioorg Med Chem 2005;13:6810–6822. 183. Khanna S, Madan M, Vangoori A, Banerjee R, Thaimattam R, Jafar Sadik Basha SK, Ramesh M, Casturi SR, Pal M. Evaluation of glycolamide esters of indomethacin as potential cyclooxygenase-2 (COX-2) inhibitors. Bioorg Med Chem 2006;14:4820–4833. 184. Scholz M, Blobaum AL, Marnett LJ, Hey-Hawkins E. Synthesis and evaluation of carbaborane derivatives of indomethacin as cyclooxygenase inhibitors. Bioorg Med Chem 2011;19:3242–3248. 185. Romeiro NC, Leite RD, Lima LM, Cardozo SV, de Miranda AL, Fraga CA, Barreiro EJ. Synthesis, pharmacological evaluation and docking studies of new sulindac analogues. Eur J Med Chem 2009;44:1959–1971. 186. Walters MJ, Blobaum AL, Kingsley PJ, Felts AS, Sulikowski GA, Marnett LJ. The influence of double bond geometry in the inhibition of cyclooxygenases by sulindac derivatives. Bioorg Med Chem Lett 2009;19:3271–3274. 187. Kikuchi T, Okada M, Nengaki N, Furutsuka K, Wakizaka H, Okamura T, Zhang MR, Kato K. Efficient synthesis and chiral separation of 11C-labeled ibuprofen assisted by DMSO for imaging of in vivo behavior of the individual isomers by positron emission tomography. Bioorg Med Chem 2011;19:3265–3273.


60

r SUTHAR AND SHARMA

188. Palomer A, Pascual J, Cabré M, Borrás L, González G, Aparici M, Carabaza A, Cabré F, Garcı´ıa ´ D. Structure-based design of cyclooxygenase-2 selectivity into ketoprofen. Bioorg ML, Mauleon Med Chem Lett 2002;12:533–537. 189. Levoin N, Chrétien F, Lapicque F, Chapleur Y. Synthesis and biological testing of acyl-CoA– ketoprofen conjugates as selective irreversible inhibitors of COX-2. Bioorg Med Chem 2002;10:753– 757. 190. Zarghi A, Ghodsi R. Design, synthesis, and biological evaluation of ketoprofen analogs as potent cyclooxygenase-2 inhibitors. Bioorg Med Chem 2010;18:5855–5860. 191. Bayly CI, Black WC, Léger S, Ouimet N, Ouellet M, Percival MD. Structure-based design of COX-2 selectivity into flurbiprofen. Bioorg Med Chem Lett 1999;9:307–312. 192. Gupta K, Kaub CJ, Carey KN, Casillas EG, Selinsky BS, Loll PJ. Manipulation of kinetic profiles in 2-aryl propionic acid cyclooxygenase inhibitors. Bioorg Med Chem Lett 2004;14:667–671. 193. Yamakawa N, Suemasu S, Matoyama M, Tanaka KI, Katsu T, Miyata K, Okamoto Y, Otsuka M, Mizushima T. Synthesis and biological evaluation of loxoprofen derivatives. Bioorg Med Chem 2011;19:3299–3311. 194. Yamakawa N, Suemasu S, Okamoto Y, Tanaka K, Ishihara T, Asano T, Miyata K, Otsuka M, Mizushima T. Synthesis and biological evaluation of derivatives of 2-{2-fluoro-4-[(2oxocyclopentyl)methyl]phenyl}propanoic acid: Nonsteroidal anti-inflammatory drugs with low gastric ulcerogenic activity. J Med Chem 2012;55:5143–5150. 195. Kalgutkar AS, Rowlinson SW, Crews BC, Marnett LJ. Amide derivatives of meclofenamic acid as selective cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 2002;12:521–524. 196. Julémont F, de Leval X, Michaux C, Renard JF, Winum JY, Montero JL, Damas J, Dogné JM, Pirotte B. Design, synthesis, and pharmacological evaluation of pyridinic analogues of nimesulide as cyclooxygenase-2 selective inhibitors. J Med Chem 2004;47:6749–6759. 197. Michaux C, Charlier C, Julémont F, de Leval X, Dogné JM, Pirotte B, Durant F. A new potential cyclooxygenase-2 inhibitor, pyridinic analogue of nimesulide. Eur J Med Chem 2005;40:1316–1324. 198. Singh SK, Reddy PG, Rao KS, Lohray BB, Misra P, Rajjak SA, Rao YK, Venkateswarlu A. Polar substitutions in the benzenesulfonamide ring of celecoxib afford a potent 1,5-diarylpyrazole class of COX-2 inhibitors. Bioorg Med Chem Lett 2004;14:499–504. 199. Szabo´ G, Fischer J, Kis-Varga A, Gyires K. New celecoxib derivatives as anti inflammatory agents. J Med Chem 2008;51:142–147. 200. Nicoll-Griffith DA, Yergey JA, Trimble LA, Silva JM, Li C, Chauret N, Gauthier JY, Grimm E, Léger S, Roy P, Thérien M, Wang Z, Prasit P, Zamboni R, Young RN, Brideau C, Chan CC, Mancini J, Riendeau D. Synthesis, characterization, and activity of metabolites derived from the cyclooxygenase-2 inhibitor rofecoxib (MK-0966, VioxxTM). Bioorg Med Chem Lett 2000;10:2683– 2686. 201. Rahim MA, Rao PN, Knaus EE. Isomeric acetoxy analogues of rofecoxib: A novel class of highly potent and selective cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 2002;12:2753–2756. 202. Zarghi A, Praveen PN, Knaus EE. Synthesis and biological evaluation of methanesulfonamide analogues of rofecoxib: Replacement of methanesulfonyl by methanesulfonamido decreases cyclooxygenase-2 selectivity. Bioorg Med Chem 2007;15:1056–1061. 203. Navidpour L, Amini M, Shafaroodi H, Abdi K, Ghahremani MH, Dehpour AR, Shafiee A. Design and synthesis of new water-soluble tetrazolide derivatives of celecoxib and rofecoxib as selective cyclooxygenase-2 (COX-2) inhibitors. Bioorg Med Chem Lett 2006;16:4483–4487. 204. Talley JJ, Brown DL, Carter JS, Graneto MJ, Koboldt CM, Masferrer JL, Perkins WE, Rogers RS, Shaffer AF, Zhang YY, Zweifel BS, Seibert K. 4-[5-Methyl-3-phenylisoxazol-4yl]-benzenesulfonamide, valdecoxib: A potent and selective inhibitor of COX-2. J Med Chem 2000;43:775–777. 205. Talley JJ, Bertenshaw SR, Brown DL, Carter JS, Graneto MJ, Kellogg MS, Koboldt CM, Yuan J, Zhang YY, Seibert K. N-[[(5-methyl-3-phenylisoxazol-4-yl)-phenyl]sulfonyl] propanamide, sodium



206. 207. 208. 209. 210.

211. 212.

213.

214. 215. 216.

217.

218.

219.

220.

221.

222. 223.

r 61

salt, parecoxib sodium: A potent and selective inhibitor of COX-2 for parenteral administration. J Med Chem 2000;43:1661–1663. Estes LL, Fuhs DW, Heaton AH, Butwinick CS. Gastric ulcer perforation, associated with the use of injectable ketorolac. Ann Pharmacother 1993;27:42–43. Henry D, Dobson A, Turner C. Variability in the risk of major gastrointestinal complications from nonaspirin nonsteroidal anti-inflammatory drugs. Gastroenterology 1993;10:1078–1088. Wallace JL, McKnight GW. Characterization of a simple animal model for nonsteroidal antiinflammatory drug induced antral ulcer. Can J Physiol Pharmacol 1993;71:447–452. Brune K, Nuernberg B, Schneider HT. Biliary elimination of aspirin after oral and intravenous administration in patients. Agents Actions 1993;44:51–57. Whittle BJ, Hansen D, Salmon JA. Gastric ulcer formation and cyclo-oxygenase inhibition in cat antrum follows parenteral administration of aspirin but not salicylate. Eur J Pharmacol 1985;116:153–157. Davies NM. Sustained release and enteric coated NSAIDs: Are they really GI safe? J Pharm Pharm Sci 1999;2:5–14. Endo H, Sakai E, Higurashi T, Yamada E, Ohkubo H, Iida H, Koide T, Yoneda M, Abe Y, Inamori M, Hosono K, Takahashi H, Kubota K, Nakajima A. Differences in the severity of small bowel mucosal injury based on the type of aspirin as evaluated by capsule endoscopy. Dig Liver Dis 2012;44:833–838. Di Nunno L, Vitale P, Scilimati A, Tacconelli S, Patrignani P. Novel synthesis of 3,4-diarylisoxazole analogues of valdecoxib: Reversal cyclooxygenase-2 selectivity by sulfonamide group removal. J Med Chem 2004;47:4881–4890. Chen XH, Bai JY, Shen F, Bai AP, Guo ZR, Cheng GF. Imrecoxib: A novel and selective cyclooxygenase 2 inhibitor with anti-inflammatory effect. Acta Pharmacol Sin 2004;25:927–931. Feng Z, Chu F, Guo Z, Sun P. Synthesis and anti-inflammatory activity of the major metabolites of imrecoxib. Bioorg Med Chem Lett 2009;19:2270–2272. Riendeau D, Percival MD, Brideau C, Charleson S, Dubé D, Ethier D, Falgueyret JP, Friesen RW, Gordon R, Greig G, Guay J, Mancini J, Ouellet M, Wong E, Xu L, Boyce S, Visco D, Girard Y, Prasit P, Zamboni R, Rodger IW, Gresser M, Ford-Hutchinson AW, Young RN, Chan CC. Etoricoxib (MK-0663): Preclinical profile and comparison with other agents that selectively inhibit cyclooxygenase-2. J Pharmacol Exp Ther 2001;296:558–566. Bertinaria M, Shaikh MA, Buccellati C, Cena C, Rolando B, Lazzarato L, Fruttero R, Gasco A, Hoxha M, Capra V, Sala A, Rovati GE. Designing multitarget anti-inflammatory agents: Chemical modulation of the lumiracoxib structure toward dual thromboxane antagonists-COX-2 inhibitors. ChemMedChem 2012;7:1647–1660. Liedtke AJ, Crews BC, Daniel CM, Blobaum AL, Kingsley PJ, Ghebreselasie K, Marnett LJ. Cyclooxygenase-1-selective inhibitors based on the (E)-2 -des-methyl-sulindac sulfide scaffold. J Med Chem 2012;55:2287–2300. Calvello R, Panaro MA, Carbone ML, Cianciulli A, Perrone MG, Vitale P, Malerba P, Scilimati A. Novel selective COX-1 inhibitors suppress neuroinflammatory mediators in LPS-stimulated N13 microglial cells. Pharmacol Res 2012;65:137–148. Choi SH, Aid S, Caracciolo L, Minami SS, Niikura T, Matsuoka Y, Turner RS, Mattson MP, Bosetti F. Cyclooxygenase-1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer’s disease. J Neurochem 2013;124:59–68. Martel-Pelletier J, Lajeunesse D, Reboul P, Pelletier JP. Therapeutic role of dual inhibitors of 5LOX and COX, selective and non-selective non-steroidal anti-inflammatory drugs. Ann Rheum Dis 2003;62:501–509. Becker JC, Domschke W, Pohle T. Current approaches to prevent NSAID-induced gastropathy– COX selectivity and beyond. Br J Clin Pharmacol 2004;58:587–600. McCafferty DM, Granger DN, Wallace JL. Indomethacin-induced gastric injury and leukocyte adherence in arthritic versus healthy rats. Gastroenterology 1995;109:1173–1180. Medicinal Research Reviews DOI 10.1002/med

62

r SUTHAR AND SHARMA

224. Leval X, Julemont F, Delarge J, Pirotte B, Dogne JM. New trends in dual 5-LOX/COX inhibition. Curr Med Chem 2002;9:941–962. 225. Kolasa T, Brooks CD, Rodriques KE, Summers JB, Dellaria JF, Hulkower KI, Bouska J, Bell RL, Carter GW. Nonsteroidal anti-inflammatory drugs as scaffolds for the design of 5-lipoxygenase inhibitors. J Med Chem 1997;40:819–824. 226. Chowdhury MA, Abdellatif KR, Dong Y, Das D, Yu G, Velázquez CA, Suresh MR, Knaus EE. Synthesis and biological evaluation of salicylic acid and N-acetyl-2-carboxybenzenesulfonamide regioisomers possessing a N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore: Dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity. Bioorg Med Chem Lett 2009;19:6855–6861. 227. Chowdhury MA, Abdellatif KR, Dong Y, Das D, Suresh MR, Knaus EE. Synthesis of celecoxib analogs that possess a N-hydroxypyrid-2(1H)one 5-lipoxygenase pharmacophore: Biological evaluation as dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity. Bioorg Med Chem Lett 2008;18:6138–6141. 228. Chowdhury MA, Abdellatif KR, Dong Y, Das D, Suresh MR, Knaus EE. Synthesis of celecoxib analogues possessing a N-difluoromethyl-1,2-dihydropyrid-2-one 5-lipoxygenase pharmacophore: Biological evaluation as dual Inhibitors of cyclooxygenases and 5-lipoxygenase with antiinflammatory activity. J Med Chem 2009;52:1525–1529. 229. Chen QH, Rao PN, Knaus EE. Synthesis and biological evaluation of a novel class of rofecoxib analogues as dual inhibitors of cyclooxygenases (COXs) and lipoxygenases (LOXs). Bioorg Med Chem 2006;14:7898–7909. 230. Elkady M, Nieß R, Schaible AM, Bauer J, Luderer S, Ambrosi G, Werz O, Laufer SA. Modified acidic nonsteroidal anti-inflammatory drugs as dual inhibitors of mPGES-1 and 5-LOX. J Med Chem 2012;55:8958–8962. 231. Xie W, Chipman JG, Robertson DL, Erikson RL, Simmons DL. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci USA 1991;88:2692–2696. 232. Vane JR, Mitchell JA, Appleton I, Tomlinson A, Bishop-Bailey D, Croxtall J, Willoughby DA. Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation. Proc Natl Acad Sci USA 1994;91:2046–2050. 233. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343:1520–1528. 234. Hippisley-Cox J, Coupland C, Logan R. Risk of adverse gastrointestinal outcomes in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: Population based nested case-control analysis. BMJ 2005;331:1310–1316. 235. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF, Burr AM, Zhao WW, Kent JD, Lefkowith JB, Verburg KM, Geis GS. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS study: A randomized controlled trial. Celecoxib Longterm Arthritis Safety Study. JAMA 2000;284:1247–1255. 236. Abraham NS, El-Serag HB, Hartman C, Richardson P, Deswal A. Cyclooxygenase-2 selectivity of non-steroidal anti-inflammatory drugs and the risk of myocardial infarction and cerebrovascular accident. Aliment Pharmacol Ther 2007;25:913–924. 237. Fitzgerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004;351:1709–1711. 238. Gretzer B, Maricic N, Respondek M, Schuligoi R, Peskar BM. Effects of specific inhibition of cyclo-oxygenase-1 and cyclo-oxygenase-2 in the rat stomach with normal mucosa and after acid challenge. Br J Pharmacol 2001;132:1565–1573. 239. Maricic N, Ehrlich K, Gretzer B, Schuligoi R, Respondek M, Peskar BM. Selective cyclooxygenase-2 inhibitors aggravate ischaemia-reperfusion injury in the rat stomach. Br J Pharmacol 1999;128:1659– 1666. Medicinal Research Reviews DOI 10.1002/med


r 63

240. Davies NM, Sharkey KA, Asfaha S, MacNaughton WK, Wallace JL. Aspirin induces a rapid up-regulation of cyclooxygenase-2 expression in the rat stomach. Aliment Pharmacol Ther 1997;11:1101–1108. 241. Fiorucci S, Menezes de Lima O, Mencarelli A, Palazzetti B, Distrutti E, McKnight W, Dicay M, Ma L, Romano M, Morelli A, Wallace JL. Cyclooxygenase-2-derived lipoxin A4 increases gastric resistance to aspirin-induced damage. Gastroenterology 2002;123:1598–1606. 242. Langenbach R, Morham SG, Tiano HF, Loftin CD, Ghanayem BI, Chulada PC, Mahler JF, Lee CA, Goulding EH, Kluckman KD, Kim HS, Smithies O. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell 1995;83:483–492. 243. Wallace JL, Bak A, McKnight W, Asfaha S, Sharkey KA, Mac- Naughton WK. Cyclooxygenase-1 contributes to inflammatory responses in rats and mice: Implications for GI toxicity. Gastroenterology 1998;115:101–109. 244. Barnett K, Bell CJ, McKnight W, Dicay M, Sharkey KA, Wallace JL. Role of cyclooxygenase-2 in modulating gastric acid secretion in the normal and inflamed rat stomach. Am J Physiol Gastrointest Liver Physiol 2000;279:G1292–G1297. 245. Takeuchi K, Aihara E, Sasaki Y, Nomura Y, Ise F. Involvement of cyclooxygenase-1, prostaglandin E2 and EP1 receptors in acid induced HCO3- secretion in the stomach. J Physiol Pharmacol 2006;57:661–676. 246. Darling RL, Romero JJ, Dial EJ, Akunda JK, Langenbach R, Lichtenberger LM. The effects of aspirin on gastric mucosal integrity, surface hydrophobicity, prostaglandin metabolism in cyclooxygenase knockout mice. Gastroenterology 2004;127:94–104. 247. Tanaka A, Hase S, Miyazawa T, Takeuchi K. Up-regulation of cyclooxygenase-2 by inhibition of cyclooxygenase-1: A key to nonsteroidal anti-inflammatory drug-induced intestinal damage. J Pharmacol Exp Ther 2002;300:754–761. 248. Takano T, Fiore S, Maddox JF, Brady HR, Petasis NA, Serhan CN. Aspirin-triggered 15-epi-lipoxin A4 (LXA4) and LXA4 stable analogues are potent inhibitors of acute inflammation: Evidence for anti-inflammatory receptors. J Exp Med 1997;185:1693–1704. 249. Serhan CN, Oliw E. Unorthodox routes to prostanoid formation: New twists in cyclooxygenaseinitiated pathways. J Clin Invest 2001;107:1481–1489. 250. Fiorucci S, Santucci L, Wallace JL, Sardina M, Fransioli R, Romano M, del Soldato P, Morelli A. Interaction of a selective cyclooxygenase-2 inhibitor with aspirin and NO-releasing aspirin in the human gastric mucosa. Proc Natl Acad Sci USA 2003;100:10937–10941. 251. Souza MH, de Lima OM Jr, Zamuner SR, Fiorucci S, Wallace JL. Gastritis increases resistance to aspirin-induced mucosal injury via COX-2-mediated lipoxin synthesis. Am J Physiol Gastrointest Liver Physiol 2003;285:G54–G61. 252. Perretti M, Chiang N, La M, Fierro IM, Marullo S, Getting SJ, Solito E, Serhan CN. Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor. Nat Med 2002;8:1296–1302. 253. Weylandt KH, Kang JX, Wiedenmann B, Baumgart DC. Lipoxins and resolvins in inflammatory bowel disease. Inflamm Bowel Dis 2007;13:797–799. 254. McMahon B, Godson C. Lipoxins: Endogenous regulators of inflammation. Am J Physiol Renal Physiol 2004;286:F189–F201. 255. Gewirtz A. Lipoxin analogs: Novel anti-inflammatory mediators. Curr Opin Investig Drugs 2005;6:1112–1115. 256. LT-NS001. Available at: http://www.logicaltx.com/product-pipeline/lt-ns001.php.html. 257. Goldstein JL, Jungwirthová A, David J, Spindel E, Bouchner L, Peˇsek F, Searle S, Skopek J, Grim J, Ulˇc I, Sewell KL. Clinical trial: Endoscopic evaluation of naproxen etemesil, a naproxen prodrug, vs. naproxen—A proof-of-concept, randomized, double-blind, active-comparator study. Aliment Pharmacol Ther 2010;32:1091–1101.


64

r SUTHAR AND SHARMA

258. Fahmy HH, El-Eraky W. Synthesis and evaluation of the analgesic and antiinflammatory activities of O-substituted salicylamides. Arch Pharm Res 2001;24:171–179. 259. Abdel-Alim AA, El-Shorbagi AN, Abdel-Moty SG, Abdel-Allah HH. Synthesis and antiinflammatory testing of some new compounds incorporating 5-aminosalicylic acid (5-ASA) as potential prodrugs. Arch Pharm Res 2005;28:637–647. 260. Kaila N, Janz K, DeBernardo S, Bedard PW, Camphausen RT, Tam S, Tsao DH, Keith JC Jr, Nickerson-Nutter C, Shilling A, Young-Sciame R, Wang Q. Synthesis and biological evaluation of quinoline salicylic acids as P-selectin antagonists. J Med Chem 2007;50:21–39. 261. Moser P, Sallmann A, Wiesenberg I. Synthesis and quantitative structure-activity relationships of diclofenac analogues. J Med Chem 1990;33:2358–2368. 262. Bhandari SV, Bothara KG, Raut MK, Patil AA, Sarkate AP, Mokale VJ. Design, synthesis and evaluation of antiinflammatory, analgesic and ulcerogenicity studies of novel S-substituted phenacyl1,3,4-oxadiazole-2-thiol and Schiff bases of diclofenac acid as nonulcerogenic derivatives. Bioorg Med Chem 2008;16:1822–1831. 263. Bandgar BP, Sarangdhar RJ, Viswakarma S, Ahamed FA. Synthesis and biological evaluation of orally active prodrugs of indomethacin. J Med Chem 2011;54:1191–1201. 264. Arisawa M, Kasaya Y, Obata T, Sasaki T, Nakamura T, Araki T, Yamamoto K, Sasaki A, Yamano A, Ito M, Abe H, Ito Y, Shuto S. Design and synthesis of indomethacin analogues that inhibit P-glycoprotein and/or multidrug resistant protein without COX inhibitory activity. J Med Chem 2012;55:8152–8163. 265. Cocco MT, Congiu C, Onnis V, Morelli M, Cauli O. Synthesis of ibuprofen heterocyclic amides and investigation of their analgesic and toxicological properties. Eur J Med Chem 2003;38:513–518. 266. Khan MS, Akhter M. Synthesis, pharmacological activity and hydrolytic behavior of glyceride prodrugs of ibuprofen. Eur J Med Chem 2005;40:371–376. 267. Chatterjee NR, Kulkarni AA, Ghulekar SP. Synthesis, pharmacological activity and hydrolytic behavior of ethylenediamine and benzathine conjugates of ibuprofen. Eur J Med Chem 2008;43:2819– 2823. 268. Sujith KV, Rao JN, Shetty P, Kalluraya B. Regioselective reaction: Synthesis and pharmacological study of Mannich bases containing ibuprofen moiety. Eur J Med Chem 2009;44:3697–3702. 269. Barsoum F, Georgey H, Abdel-Gawad N. Anti-inflammatory activity and PGE2 inhibitory properties of novel phenylcarbamoylmethyl ester-containing compounds. Molecules 2009;14:667–681. 270. Amir M, Kumar H, Javed SA. Synthesis and pharmacological evaluation of condensed heterocyclic 6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives of naproxen. Bioorg Med Chem Lett 2007;17:4504–4508. 271. Kumar S, Tyagi DK, Gupta A. Synthesis, characterization and pharmacological activity of ester prodrugs of naproxen. Asian J Pharm Clin Res 2010;3:208–211. 272. Wei J, Shi J, Zhang J, He G, Pan J, He J, Zhou R, Guo L, Ouyang L. Design, synthesis and biological evaluation of enzymatically cleavable NSAIDs prodrugs derived from self-immolative dendritic scaffolds for the treatment of inflammatory diseases. Bioorg Med Chem 2013;21:4192– 4200. 273. Sharma S, Srivastava VK, Kumar A. Newer N-substituted anthranilic acid derivatives as potent anti-inflammatory agents. Eur J Med Chem 2002;37:689–697. 274. Abdul Razzak NA. Design and synthesis of new mefenamic acid derivatives as anti-inflammatory agents. J Al-Nahrain Univ 2011;14:38–44. 275. Omar FA. Cyclic amide derivatives as potential prodrugs. Synthesis and evaluation of Nhydroxymethylphthalimide esters of some non-steroidal anti-inflammatory carboxylic acid drugs. Eur J Med Chem 1998;33:123–131. 276. Mahfouz NM, Omar FA, Aboul-Fadl T. Cyclic amide derivatives as potential prodrugs II: Nhydroxymethylsuccinimide-/isatin esters of some NSAIDs as prodrugs with an improved therapeutic index. Eur J Med Chem 1999;34:551–562.



r 65

277. Mendes E, Furtado T, Neres J, Iley J, Jarvinen T, Rautio J, Moreira R. Synthesis, stability and in vitro dermal evaluation of aminocarbonyloxymethyl esters as prodrugs of carboxylic acid agents. Bioorg Med Chem 2002;10:809–816. 278. Yang SF, Hsieh YS, Lue KH, Chu SH, Chang IC, Lu KH. Effects of nonsteroidal anti-inflammatory drugs on the expression of urokinase plasminogen activator and inhibitor and gelatinases in the early osteoarthritic knee of humans. Clin Biochem 2008;41:109–116. 279. Yadav MR, Pawar VP, Marvaniya SM, Halen PK, Giridhar R, Mishra AK. Site specific chemical delivery of NSAIDs to inflamed joints: Synthesis, biological activity and c-imaging studies of quaternary ammonium salts of tropinol esters of some NSAIDs or their active metabolites. Bioorg Med Chem 2008;16:9443–9449. 280. Li CJ, Chang JK, Chou CH, Wang GJ, Ho ML. The PI3K/Akt/FOXO3a/p27Kip1 signaling contributes to anti-inflammatory drug-suppressed proliferation of human osteoblasts. Biochem Pharmacol 2010;79:926–937. 281. Cai J, Duan Y, Yu J, Chen J, Chao M, Ji M. Bone-targeting glycol and NSAIDS ester prodrugs of rhein: Synthesis, hydroxyapatite affinity, stability, anti-inflammatory, ulcerogenicity index and pharmacokinetics studies. Eur J Med Chem 2012;55:409–419. 282. Abdel-Azeem AZ, Abdel-Hafez AA, El-Karamany GS, Farag HH. Chlorzoxazone esters of some non-steroidal anti-inflammatory (NSAI) carboxylic acids as mutual prodrugs: Design, synthesis, pharmacological investigations and docking studies. Bioorg Med Chem 2009;17:3665–3670. 283. Verma A, Das N, Dhanawat M, Shrivastava SK. Conjugation of some NSAIDs with 5-phenyl-2aminothiazole for reduced ulcerogenicity. Thai J Pharm Sci 2010;34:49–57. ¨ ¨ BC, Alkan DA, Ercan N, Ozkan 284. Uluda˘g MO, Ergun GY, Bano˘glu E. Stable ester and amide conjugates of some NSAIDs as analgesic and antiinflammatory compounds with improved biological activity. Turk J Chem 2011;35:427–439. 285. Mahdi MF, Alsaad HN. Design, synthesis and hydrolytic behavior of mutual prodrugs of NSAIDs with gabapentin using glycol spacers. Pharmaceuticals 2012;5:1080–1091. 286. Mahdi MF, Abdul Razzak NA, Omer TN, Hadi MK. Design and synthesis of possible mutual prodrugs by coupling of NSAIDs with sulfa drugs by using glycolic acid as spacer. Pharmacie Globale (IJCP) 2012;2:1–4. 287. Mahdi MF, Mohammed MH, Jassim AA. Design, synthesis and preliminary pharmacological evaluation of new non-steroidal anti-inflammatory agents having a 4-(methylsulfonyl) aniline pharmacophore. Molecules 2012;17:1751–1763. 288. Gund M, Khan FR, Khanna A, Krishnakumar V. Nicotinic acid conjugates of nonsteroidal anti-inflammatory drugs (NSAIDs) and their anti-inflammatory properties. Eur J Pharm Sci 2013;49:227–232. 289. Lanas A, Scarpignato C. Microbial flora in NSAID-induced intestinal damage: A role for antibiotics? Digestion 2006;73(Suppl 1):136–150. 290. Carson JL, Strom BL, Morse ML, West SL, Soper KA, Stolley PD, Jones JK. The relative gastrointestinal toxicity of the nonsteroidal anti-inflammatory drugs. Arch Intern Med 1987;147:1054–1059. 291. Chan FK, Sung JJ, Ching JY, Wu JC, Lee YT, Leung WK, Hui Y, Chan LY, Lai AC, Chung SC. Randomized trial of low-dose misoprostol and naproxen vs. nabumetone to prevent recurrent upper gastrointestinal haemorrhage in users of non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther 2001;15:19–24. 292. Graham DY. Endoscopic ulcers are neither meaningful nor validated as a surrogate for clinically significant upper gastrointestinal harm. Clin Gastroenterol Hepatol 2009;7:1147–1150. 293. NSAID prodrug platform. Available at: http://www.logicaltx.com/product-pipeline/index.html. 294. Goldstein JL, Eisen GM, Lewis B, Gralnek IM, Zlotnick S, Fort JG. Video capsule endoscopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and placebo. Clin Gastroenterol Hepatol 2005;3:133–141. 295. Graham DY, Opekun AR, Willingham FF, Qureshi WA. Visible small-intestinal mucosal injury in chronic NSAID users. Clin Gastroenterol Hepatol 2005;3:55–59. Medicinal Research Reviews DOI 10.1002/med

66

r SUTHAR AND SHARMA

296. Maiden L, Thjodleifsson B, Theodors A, Gonzalez J, Bjarnason I. A quantitative analysis of NSAID-induced small bowel pathology by capsule endoscopy. Gastroenterology 2005;128:1172– 1178. 297. Fujimora S, Gudis K, Takahashi Y, Seo T, Yamada Y, Ehara A, Kobayashi T, Mitsui K, Yonezawa M, Tanaka S, Tatsuguchi A, Sakamoto C. Distribution of small intestinal mucosal injuries as a result of NSAID administration. Eur J Clin Invest 2010;40:504–510. 298. Shindo K, Fukumura M. Effect of H2-receptor antagonists on bile acid metabolism. J Investig Med 1995;43:170–177. 299. Shindo K, Machida M, Fukumura M, Koide K, Yamazaki R. Omeprazole induces altered bile acid metabolism. Gut 1998;42:266–271. 300. Begley M, Gahan CG, Hill C. The interaction between bacteria and bile. FEMS Microbiol Rev 2005;29:625–651. 301. Martinez-Augustin O, Sanchez de Medina F. Intestinal bile acid physiology and pathophysiology. World J Gastroenterol 2008;14:5630–5640. 302. Hofmann AF. The continuing importance of bile acids in liver and intestinal disease. Arch Intern Med 1999;159:2647–2658. 303. Wallace JL, Denou E, Vong L, Syer S, McKnight W, Jury J, Verdu EF, Bercik P, Collins SM, Bolla M, Ongini E. Proton pump inhibitors and low-dose aspirin markedly exacerbate NSAID-induced small intestinal injury: Link to dysbiosis?. Gastroenterology 2011;140:S-87. 304. Why an NSAID prodrug? Available at: http://www.logicaltx.com/index.html. 305. Blobaum AL, Marnett LJ. Structural and functional basis of cyclooxygenase inhibition. J Med Chem 2007;50:1425–1441. 306. Roth GJ, Machuga ET, Ozols J. Isolation and covalent structure of the aspirin-modified, active-site region of prostaglandin synthetase. Biochemistry 1983;22:4672–4675. 307. DeWitt DL, el-Harith EA, Kraemer SA, Andrews MJ, Yao EF, Armstrong RL, Smith WL. The aspirin and hemebinding sites of ovine and murine prostaglandin endoperoxide synthases. J Biol Chem 1990;265:5192–5198. 308. Mancini JA, Riendeau D, Falgueyret JP, Vickers PJ, O’Neill GP. Arginine 120 of prostaglandin G/H synthase-1 is required for the inhibition by nonsteroidal anti-inflammatory drugs containing a carboxylic acid moiety. J Biol Chem 1995;270:29372–29377. 309. Greig GM, Francis DA, Falgueyret JP, Ouellet M, Percival MD, Roy P, Bayly C, Mancini JA, O’Neill GP. The interaction of arginine 106 of human prostaglandin G/H synthase-2 with inhibitors is not a universal component of inhibition mediated by nonsteroidal anti-inflammatory drugs. Mol Pharmacol 1997;52:829–838. 310. Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature 1996;384:644–648. 311. Clark K, Kulathila R, Koehn J, Rieffel S, Strauss A, Hu S, Kalfoglou M, Szeto D, Lasala D, Sabio M, Wang X, Marshall P. Crystal structure of the lumiracoxib: Cyclooxygenase-2 complex (abstract). 228th American Chemical Society National Meeting (Division of Biological Chemistry), Philadelphia, PA, 2004;178. 312. Fabiola GF, Pattabhi V, Nagarajan K. Structural basis for selective inhibition of COX-2 by nimesulide. Bioorg Med Chem 1998;6:2337–2344. 313. Guo Q, Wang LH, Ruan KH, Kulmacz RJ. Role of Val509 in time-dependent inhibition of human prostaglandin H synthase-2 cyclooxygenase activity by isoform-selective agents. J Biol Chem 1996;271:19134–19139. 314. Gierse JK, McDonald JJ, Hauser SD, Rangwala SH, Koboldt CM, Seibert K. A single amino acid difference between cyclooxygenase-1 (COX-1) and -2 (COX-2) reverses the selectivity of COX-2 specific inhibitors. J Biol Chem 1996;271:15810–15814. 315. Price ML, Jorgensen WL. Rationale for the observed COX-2/COX-1 selectivity of celecoxib from Monte Carlo simulations. Bioorg Med Chem Lett 2001;11:1541–1544. Medicinal Research Reviews DOI 10.1002/med


r 67

316. Sharma BK, Singh P, Shekhawat M, Pilania P. A rationale for the activity profile of benzenesulfonamide derivatives as cyclooxygenase (COX) inhibitors. Eur J Med Chem 2010;45:2389–2395. 317. An innovative approach to nitric oxide donation. Available at: http://www.nicox.com/ index.php/en/rd/other-therapeutic-areas/cardiovascular. 318. Developed for the relief of the signs and symptoms of osteoarthritis. Available at: http://www.nicox.com/index.php/en/rd/other-therapeutic-areas/naproxcinod-osteoarthritis. 319. Nicox to re-focus naproxcinod on Duchenne muscular dystrophy. Available at: http://www.drugs.com/nda/naproxcinod_140214.html. 320. ATB-346 (lead drug). Available at: http://www.antibethera.com/s/ATB-346.asp. 321. GI-Safer NSAID Technology & Product Pipeline—With PLxGuardTM . Available at: http://www.plxpharma.com/prodDev.htm. 322. Wallace JL, Ferraz JG. New pharmacologic therapies in gastrointestinal disease. Gastroenterol Clin North Am 2010;39:709–720.

Sharad Kumar Suthar is working as a Senior Research Fellow in Indian Council of Medical Research sponsored project with Dr. Manu Sharma at Department of Pharmacy, Jaypee University of Information Technology, Waknaghat, India. He carried out his Ph.D. work (2010–2014) under supervision of Dr. Manu Sharma, where he was involved in design and synthesis of lantadene– NSAID hybrid compounds and other medicinal agents for anticancer and anti-inflammatory activities. Before that he obtained M. Pharm. (Pharmaceutical Chemistry) in 2010 from Manipal College of Pharmaceutical Sciences, Manipal, India and B. Pharm. in 2008 from University of Pune, India. His research interests involve exploring novel anticancer and anti-inflammatory agents with improved potency and safety. Manu Sharma leads the Natural Product Chemistry Research Group and is Assistant Professor in the Department of Pharmacy at the Jaypee University of Information Technology, Waknaghat, India. He obtained his Ph.D. (Medicinal Chemistry) from Panjab University Chandigarh in 2008 (under the supervision of the late Professor P. D. Sharma). For the last 10 years, he has been working in the area of phytochemistry of pentacyclic triterpenoids of weed Lantana camara L. and catechins. He is also working in the area of micronutrient receptor-mediated endocytosis-based selective tumor targeting agents and gastro-sparing NSAIDs.


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Recent developments in antiviral agents against enterovirus 71 infection.

Aspirin and other NSAIDs as chemoprevention agents in melanoma.

A review on recent developments of indole-containing antiviral agents.

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Avian Paramyxoviridae--recent developments.