A comprehensive patents review on cannabinoid 1 receptor antagonists as antiobesity agents.

Review

Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Nyu Medical Center on 07/23/15 For personal use only.

A comprehensive patents review on cannabinoid 1 receptor antagonists as antiobesity agents 1.

Introduction

2.

CB1 receptor antagonists

3.

Expert opinion

Mayank Kumar Sharma, Prashant R Murumkar, Mahesh A Barmade, Rajani Giridhar & Mange Ram Yadav† The M. S. University of Baroda, Pharmacy Department, Faculty of Technology and Engineering, Kalabhavan, Vadodara, India

Introduction: Obesity is a rapidly expanding worldwide health problem. Various targets are investigated presently for the treatment of obesity, but there remains an unmet need for an effective drug therapy with acceptable efficacy levels and reduced side effects. Targeting peripherally located cannabinoid 1 (CB1) receptors is an attractive strategy as these receptors play a vital role in energy homeostasis. Areas covered: CB1 receptor antagonists constitute one of the most important categories of compounds of interest for the control of obesity. In this review, the authors focus on recent advances (since 2007) in diverse chemical classes of patented compounds belonging to the category of CB1 receptor antagonists. Expert opinion: Safer CB1 receptor antagonists for the treatment of obesity can be discovered by developing such compounds that act peripherally. Increasing the polar service area, decreasing the lipophilicity and designing of neutral antagonists and allosteric inhibitors are some interesting strategies that could offer promising results. Keywords: cannabinoid, CB1 receptor antagonists, endocannabinoid system, obesity, peripherally acting, rimonabant Expert Opin. Ther. Patents [Early Online]

1.

Introduction

Obesity and overweight problems have increased astonishingly worldwide in the last three decades in both adults (28% increase) and children (47% increase). The number of obese and overweight cases was 857 million in 1980, which increased to 2.1 billion in 2013 [1]. Obesity, a result of imbalance in energy homeostasis between nutrient intake and expenditure, is characterized by excessive fat accumulation in the body. Overweight persons have body mass index (BMI) ‡ 25, whereas BMI ‡ 30 in obese persons. According to WHO, about 44% of diabetes mellitus, 23% of ischemic heart diseases and 7 -- 41% of certain types of cancers are globally attributed to overweight and obesity. It is revealed that the condition is likely to worsen in the coming years [2]. Unfortunately, current obesity treatment options are highly limited. Orlistat (1) marketed in 1999 for the treatment of obesity is acting peripherally as a gastrointestinal and pancreatic lipase inhibitor. It is a moderately effective drug having significant gastrointestinal side effects. In 2012, lorcaserin (2) was approved by US-FDA on a refiling while it was rejected earlier in 2010 due to its tendency to cause tumor growth in preclinical studies [3-5]. Qsymia, a combination of phentermine and topiramate, was approved in July 2012 [6], and recently, US-FDA approved contrave, a combination of bupropion and naltrexone in September 2014 [7]. Some shortterm--use drugs like phentermine and diethylpropion were also approved by FDA 10.1517/13543776.2015.1064898 © 2015 Informa UK, Ltd. ISSN 1354-3776, e-ISSN 1744-7674 All rights reserved: reproduction in whole or in part not permitted

1

M. K. Sharma et al.

Article highlights. . .

.

.


.

One third of the world population is suffering from obesity and overweight problems. Targeting the peripherally located cannabinoid 1 (CB1) receptor selectively is an attractive strategy for the management of obesity. A brief summary on endocannabinoids, cannabinoid receptors, role of CB1 receptor in obesity, and selectivity issue has been given. The review covers various strategies used for the development of peripherally acting selective CB1 receptor antagonists. The review is focused on diverse classes of CB1 receptor antagonists patented in the field of medicinal chemistry since 2007 onward.

This box summarizes key points contained in the article.

but these were not so effective. Drugs like rimonabant (3) [8], a cannabinoid 1 (CB1) receptor antagonist, and sibutramine (4), a dual serotonin-norepinephrine reuptake inhibitor, were withdrawn from the market due to their side effects [3-5]. Other strategies such as use of cholecystokinin agonists, glucagon-like peptide-1 analogs, amylin analogs, neuropeptide Y agonists, peptide YY agonists, ghrelin antagonists, MCH1 receptor antagonists, MC4 receptor agonists, 5-HT2B receptor agonists, 5-HT6 receptor antagonists, dopamine agonists, µ-opioid receptor antagonists, agouti-related protein inhibitors and methionine aminopeptidase inhibitors have also been identified for the treatment of obesity [9]. It has been observed that the biggest challenges in developing antiobesity drugs are their poor safety profile and moderate efficacy. Despite the rimonabant withdrawal and termination of other CB1 receptor antagonists, there are still opportunities to explore CB1 receptor antagonists for the treatment of obesity. Me 10 O

O O

Me

H N

NH

H Cl

O

4

O

Me

Me

Me (1)

(2)

Cl

Me

Me

Me HN N N N Cl

O

Me

N Me Cl

Cl (3)

(4)

The endocannabinoid system (ECS) consists of endocannabinoids, receptors and their synthesizing and degrading enzymes [10]. Endocannabinoids such as anandamide and 2-arachidonoylglycerol bind with cannabinoid receptor. Enzymes like N-acyl-phosphatidylethanolamine-selective phospholipase D and diacylglycerol lipases are involved in the synthesis of endocannabinoids, whereas fatty acid amide 2

hydrolase and monoacylglycerol lipase are involved in the degradation [11]. The ECS plays a vital role in the regulation of feeding behavior, metabolism and energy balance. ECS is overactive in obesity, with increased level of endocannabinoids in plasma and several tissues of obese patients and in animal models of obesity [12]. Thus, blockade of CB1 receptor is one of the potential strategies for the treatment of obesity. Rimonabant was approved in 2006 as an antiobesity agent in Europe but it was withdrawn from the market in 2008 due to its CNS adverse side effects [13-15] For avoiding the CNS side effects, peripheral CB1 receptor antagonists were designed proving very beneficial as these were claimed to have no/little side effects [16,17]. Two types of cannabinoid receptors are identified, i.e., CB1 [18] and CB2, belonging to G-protein-coupled receptors [19-21], having 44% amino acid sequence identity [22]. Activation of CB1 receptors inhibits adenylate cyclase, which lowers the production of cAMP that attenuates the protein kinase A (PKA) pathway. PKA decreases the phosphorylation of potassium channel in the presence of cannabinoids resulting in enhanced outward potassium current. CB1 stimulation in neurons inhibits voltage-dependent calcium channels and mediates retrograde signal transduction and activates inwardly rectifying K+ channels causing decrease in neuronal excitability and thus playing a key role in regulating neurotransmitter release. Stimulation of CB1 receptors activates second messenger signaling pathway involving mitogen-activated protein kinase, extracellular signal-regulated protein kinase and NF-kb that modulate gene expression [23-26]. Activation of CB1 receptors by an agonist causes positive intrinsic activity while its binding to inverse agonist shows negative intrinsic activity. Neutral antagonists show no intrinsic activity on binding to the CB1 receptor [27]. AM4113 (Npiperidin-1-yl-2,4-dichlorophenyl-1H-pyrazole-3-carboxamide analog), a neutral antagonist, binds to CB1 receptors but it does not elicit inverse agonistic properties, i.e., no effects on cAMP production, rather it reverses the effects of agonists. It may affect feeding by blocking endogenous cannabinoid tone instead of stimulating signal transduction effects opposite to those of CB1 agonists. It is expected that AM4113 has potential to reduce appetite and food intake without causing nausea and vomiting [28]. LH-21 is another neutral antagonist with the ability to reduce food intake and weight gain in obese animals with low CNS penetration and reduced side effects than rimonabant [29]. Another study differentiates CB1 inverse agonists from neutral antagonists on intestinal motility. Ability of neutral antagonists ‘not to affect whole gut transit’ may be a key for the future development of CB1 receptor antagonists [10]. Kirilly et al. [30] have reviewed the adverse effects associated with the peripheral acting CB1 receptor antagonists like gastrointestinal disorders such as nausea, vomiting, diarrhea and dyspepsia, and nervous system disorders such as dizziness, vertigo and hypesthesia and other events like fatigue, hot flush, tendonitis and contusion.

Expert Opin. Ther. Patents (2015) 25(10)

A comprehensive patents review on cannabinoid 1 receptor antagonists as antiobesity agents

Cl

Both of the selectivity issues are important for the design of CB1 receptor antagonists as antiobesity agents. The selectivity issue is well explained elsewhere in the literature [37].

N N N Cl

2.

Me

Cl

After the discovery of rimonabant, extensive efforts were made to find out more potent and selective CB1 receptor antagonists having lesser CNS side effects. Various classes of CB1 receptor antagonists containing different scaffolds have been patented in the last few years. Reviews on the patented compounds acting on CB receptors have been published during 2000 -- 2007 [39-43]. In this article, a review of novel CB1 receptor antagonists patented since the year 2007 till date has been done. An overview of the novel invented chemical structures and relevant biological properties has been given.


LH-21

There are evidences indicating the existence of allosteric binding sites on CB1 receptors [31]. Certain compounds like Org 27569, Org 27759 and Org 29647 bind allosterically to the CB1 receptor causing conformational changes in the receptor, which enhance agonists’ affinity for the orthosteric site. It is a new approach to modulate activation of CB1 receptor by endogenously released endocannabinoid [31]. Allosteric antagonism is an alternative strategy for the development of safe CB1 receptor antagonists having certain advantages over compounds binding to orthosteric site like increased selectivity across receptor subtypes and the ability to maintain the spatial and temporal signaling profile of the endogenous ligands. PSNCBAM-1 is a novel CB1 receptor-specific allosteric antagonist that produced hypophagia and weight loss in male SD rats [32].

F

O N H

Thiophene derivatives Barth et al. [44] from Sanofi-Aventis synthesized thiophene2-carboxamide derivatives as CB1 receptor antagonist. The research group [45] extended the series and synthesized novel 4,5-diarylthiophene-2-carboxamide derivatives as CB1 recep2.1

Me

Me Cl

CB1 receptor antagonists

O N H

HN

Me N Me

HN

N Org 27569

Org 27759

Me Cl

Cl

O

O N H

HN

N

N H

N H

Org 29647

N

N

PSNCBAM-1

TFood intake is controlled in the central site by hypothalamus and limbic system, whereas peripheral effects of CB1 receptor antagonists could be mediated in several peripheral organs in which there occurs blockage of de novo lipogenesis in liver, increase in glucose uptake in muscles, adiponectin stimulation, inhibition of lipogenic enzymes, stimulation of GLUT4 and generation of futile cycles in adipose tissues, insulin regulation in pancreas and stimulation in satiety signals in gastrointestinal tract (GIT). The detailed description of these actions can be found elsewhere [33-38]. Selectivity plays a major role in the designing of CB1 receptor antagonists. Firstly, selectivity of CB1 receptor over CB2 is important. Blockage of CB2 receptors showed several side effects such as cardiometabolic and autoimmune disorders and fibrosis. Second selectivity issue is related to the peripherally located CB1 receptors over centrally located ones, due to the CNS-related side effects of inhibiting central CB1 receptors.

tor antagonists acting on central as well as peripheral sites. These compounds exhibited good in vitro activity as shown in Table 1. Brain-to-plasma ratios of 1.8 and 0.04 were observed for rimonabant (3) and compound (5), respectively, at an intravenous (iv) dose of 3 mg/kg. Rimonabant (3) and compounds (5 and 6) exhibited 100, 13 and 32% inhibition, respectively, of the binding of [3H]-CP55940 at 10 mg/kg iv doses with regard to the CB1 receptors present in the brain, indicating that the designed compounds (5 and 6) were poor entrants into the brain and act peripherally. O HO


NH2

O

S X

N

(5) X = Cl

O

(6) X = H

Cl

(5, 6)

3

M. K. Sharma et al.

Table 1. Compounds with their IC50 values in mM.


Compound 5,6 7 -- 10 14 15 -- 17 18 19,20 23 24 25,26 27 -- 30 31 -- 34 35 -- 37 38 39 40 41 42 43 44 45 46 47 48 49 -- 51 52 -- 54 55 -- 59 60 -- 64 73 -- 76 83 84 85 86 90 91 100 -- 102 105

2.2

IC50

Ref.

0.5 0.5 0.1 -- 0.5 0.01 -- 0.1 < 0.01 < 0.2 3 -- 10 0.3 -- 3 < 0.3 < 0.3 0.0001 -- 20 0.001 -- 10 0.00109 0.00179 0.0116 0.0609 0.0142 0.112 0.0841 0.00147 0.00164 0.00411 0.00087 0.5 -- 5 < 0.5 < 0.5 < 10 < 0.5 0.0105 0.00898 0.00170 0.00114 1.173 0.0116 < 10 1 -- 10

[55,56] [57,58] [60] [60] [60] [61] [63-65] [63-65] [63-65] [66] [67,68] [69] [70,71] [70,71] [70,71] [70,71] [70,71] [70,71] [70,71] [72] [72] [73] [73] [74] [74] [75] [76] [85] [88] [88] [88] [88] [91] [91] [99,100] [103-105]

Pyrrole derivatives

Novel derivatives of 4,5-diarylpyrrole-2-carboxamides having peripheral CB1 receptor antagonistic property with poor brain penetration were invented by Barth et al. [46-48]. After the administration of 3 mg/kg iv dose, the brain-to-plasma concentration ratios were observed to be 1.8 and 0.05 for rimonabant and compound (7), respectively. Percentage inhibition of [3H]-CP55940 binding in the brain was observed to be 100 and 1%, respectively, for rimonabant and compound (8). At 10 mg/kg dose, compound (8) exhibited 100% reversion effect of CP55940 on gastrointestinal transit indicating peripheral activity of the compound. Barth et al. [49-51] further reported novel 1,5-diphenylpyrrole-3-carboxamide derivatives possessing CB1 receptor antagonists’ properties with in vitro activity (IC50 £ 0.5 µM). Brain-to-plasma ratios of 1.8 and 0.06 were observed for rimonabant and compound (9), respectively, at an iv dose of 3 mg/kg each. One hundred percent and 5% inhibition of the binding of [3H]-CP55940 was observed 4

Compound 106 107 108 109 110 111 112 120 121 122 123 131,132 133,134 135 136,137 138,139 140 141 142 143 144 145 146 147 -- 149 158 -- 160 173 174 177 178 181 182 183 184 185 186 187

IC50

Ref.

0.1 -- 1 < 0.1 >1 0.01 -- 0.099 0.1 -- 0.5 0.01 0.00752 0.0004 0.001 0.001 0.002 0.01 -- 0.1 < 0.01 0.01 -- 0.1 0.001 -- 0.1 < 0.01 < 0.01 < 0.01 0.011 0.0006 0.011 0.002 0.001 < 0.01 < 0.001 0.016 0.006 0.004 0.007 3.791 3.188 3.221 0.00607 0.00124 0.4 0.001

[103-105] [103-105] [106,107] [106,107] [106,107] [106,107] [108] [114,115] [114,115] [116,117] [116,117] [123] [123] [124,125] [124,125] [124,125] [126] [126] [127] [127] [128] [128] [128] [129,130] [135] [139] [139] [141] [141] [143] [143] [143] [143] [143] [144] [144]

by rimonabant and compound (10), respectively, in the brain. In the GIT, 100% reversal of the effect of CP55940 was caused by compound (10) at a dose of 10 mg/kg po route. Thus, the designed compounds were found to possess less penetration in the brain and better peripheral distribution. O Cl

NH2

O

Cl

NH

Cl N N Me

H2N

N

O

N Me

O

HO

O

(7)

O

NH2

O F

(8)

OH HO

O

Cl

NH2

O Cl

N

Cl

N

N

O Cl

Cl


(9)

N O

Cl

Cl

(10)

NH2


2.3

showed IC50 values between 0.01 and 0.1 µM. The most active compound (18) was obtained having difluoromethoxy group attached to the fourth position and difluoropiperidinyl attached to carboxamide group at third position of the pyrazole exhibiting IC50 value less than 0.01 µM. Ahlqvist et al. [57] from Astrazeneca Ltd. reported novel sulfonate esters (19 and 20) of 1,5-diarylpyrazole-3-carboxamide. These compounds exhibited IC50 values of less than 0.2 µM, whereas some other active compounds showed IC50 values of less than 1 µM.

Pyrazole derivatives

Lange et al. [52-54] from Solvay Pharmaceuticals introduced sulfur-containing pyrazole derivatives and their S-oxidized active metabolites as selective CB1 receptor antagonists. Affinity of the synthesized compounds was determined by using membrane preparation of Chinese Hamster Ovary cells in which human CB1 receptors were stably transfected in conjunction with [3H]CP-55940. Compound (11) having methylsulfanyl group at the fourth position of the pyrazole ring in compound (11) exhibited a Ki value of 0.01 µM with

Me


O

NH

Cl

OMe

F3C

NH

OMe HN

HN

O HN N N N

N N

O

N N

O

CF3

O

Cl

Cl

(14)

Cl

Cl

O

(15)

Cl

(16)

Cl OMe HN N N N

O

OCHF2 HN N

N

O

Cl

F

O

Cl

(17) R

F

N N

F

F

(18)

O

S O O

Me N N

Cl

(19) R =

O HN N

(20) R =

Me

Cl

S

Cl

(19, 20)

CB1/CB2 ratio of 67 indicating selectivity toward CB1. Compound (12) having methylsulfinyl group at the same position showed a Ki value of 0.013 µM, indicating that these compounds (11 and 12) possessed better affinity than rimonabant (Ki = 0.025 µM). Substitution with methylsulfonyl at the same position in compound (13) showed a poor Ki value of 0.250 µM (Table 2). Cl R

(11) R = SMe HN N

N N

(12) R = SOMe

Some novel amide and hydrazide derivatives as CB1 receptor antagonists were patented by Thomas et al. [58] from Research Triangle Institute. Among the amide derivatives, compound (21) with pentyl group attached to the carboxamide at third position of pyrazole showed EC50 value of 5.270 µM in GTP-g-[35S] in whole rat brain, while among the hydrazide derivatives, a 2-methylpropanoylhydrazide (22) at the third position of pyrazole exhibited a poor EC50 value of 73.585 µM. Cl

Cl Me

O

Me O

(13) R = SO2Me Cl

N N

Cl

(11-13)

Cl

In the same year, Moritani et al. [55,56] from Tanabe Seiyaku Co. Ltd. obtained a patent related to novel pyrazole-containing potent CB1 receptor antagonists. Compound (14) with (N-ethylureido)ethoxy group attached to the fourth position of pyrazole ring exhibited an IC50 value between 0.1 and 0.5 µM, whereas compounds (15 -- 17) having 2-methoxyethoxy and methoxy groups at the same place

O N N

HN

Cl

Me

(21)

Cl

HN

Cl

Me

O HN NH2

(22)

Cooper et al. [59] from 7TM Pharma reported pyrazolecontaining CB1 receptor antagonists (23-26) in which phenyl ring at first position of rimonabant was replaced by the pyridine ring and methyl group at fourth position with tetrazole or carboxylic acid. These modifications of making the compounds more polar were helpful to design peripherally


5

M. K. Sharma et al.

Table 2. Compounds with their Ki values in µM. Ki

Ref.

0.01 0.013 0.250 0.007 0.00035 0.00089 0.056 0.294 0.036 0.00344 0.005 0.012 5.762 0.0012 0.001 £ 0.8

[59] [59] [59] [81,82] [83] [84] [86] [86] [86] [86] [87] [87] [89,90] [89,90] [89,90] [118]


Compound 11 12 13 70 71 72 77 78 79 80 81 82 87 88 89 124

Compound 125 126 147 151 152 157 161 162 163 175 176 179 180 189 190

acting CB1 receptor antagonists. In a subsequent study, Cooper et al. [60] designed modulators of CB1 receptors that suppressed the normal signaling activity of such receptors. H N N N N

OH Cl

Cl

O

N

N N

N N

Cl

N N

N N

OH

N N

Cl

Me

N N

Cl

Me

O N N CF3

O

Cl

(29)

(30)

The designed compounds exhibited varying physicochemical properties and were found to be very effective in modulating peripheral CB1 receptors and reduced central action. These compounds (27 -- 30) showed reduced propensity to 6

Me HN

O

Cl

CF3

(28)

H N N N N

N N N

O

Cl

F

H N

Me N

O

(27) N N N

Me

Me

Cl

(26)

O

Me HN

Me

Cl

(25)

Cl

O

HN

HN

F

OH

O N

CF3

Cl

OH CF3 Cl

[118] [118] [131] [131] [131] [134] [136,137] [136,137] [136,137] [140] [140] [142] [142] [145] [145]

N

N N

N

(24)

O

< 0.055 £ 0.025 0.355 0.00154 0.00193 0.264 0.08 0.0013 0.0006 0.217 0.002 0.02379 0.01917 0.0154 0.0372

O

N

Cl (23)

Cl

N N

Cl O

HN

Ref.

induce psychiatric and nervous system side effects. Carboxylic acid derivatives (27 and 28) and tetrazole-containing compounds (29 and 30) exhibited IC50 values less than 0.30 µM. H N

O

Ki

CF3

Shia et al. [61] from National Health Research Institutes, Zhunan Town (TW), discovered certain thiophene-containing pyrazole derivatives as CB1 receptor antagonists. In this work, 2,4-dichlorophenyl group was attached to the first position of




IC50 value of 0.00164 µM. Lee et al. [67,68] also discovered some novel sulfur-containing heteroaryl-pyrazole-containing compounds as effective CB1 receptor inverse agonists or antagonists. Sulfide, sulfoxide and sulfone groups were attached to the fourth position and oxadiazole and thiadiazole groups to the third position of the pyrazole ring to get a variety of compounds. Oxadiazole-containing compound (47) having methylthio group at fourth position showed IC50 value of 0.00411 µM, while the most potent compound (48) in the series was having thiadiazole and methylsulfonyl groups with IC50 value of 0.00087 µM. To design peripherally acting CB1 receptor antagonists, Receveur et al. [69] from 7TM Pharma replaced methyl group of rimonabant at fourth position of pyrazole ring by amide,

the pyrazole ring, whereas a substituted or unsubstituted thiophene ring was attached to fifth position in place of phenyl ring present in rimonabant. Different substituents like Cl, 1-pentenyl and cyclohexylethynyl, respectively, were attached to the thiophene ring in compounds (31 -- 34). Further, Shia et al. [62] attached 1,2,4-oxadiazole ring to the third position of the pyrazole ring, which showed effective binding to CB1/CB2 receptors. Phenyl ring at fifth position of the pyrazole ring of rimonabant was replaced with selenophene and thiophene rings. Selenophene-containing compound (35) and thiophene-containing compounds (36 and 37) exhibited IC50 values between 0.001 and 10 µM by inhibiting binding of [3H]CP55,940 to CB1 and CB2 receptors in the competitive binding assay. Me

Me Me

Cl

HN

S

O

S

O

N N Cl

Me

Me

S

N N

N N

HN N

HN

Cl Cl

Cl

Cl

Cl

(31)

(32)

(33)

Me

HN N

Cl

Cl

(34)

(35)

Me

Me

Me N

S N N

Me N

S

Me

N N

O N Cl

Cl

Me

O N

N N

Cl

Cl

Me

N

Se N N

Cl

Me

Me

Br

O

S

O HN

(36)

Me

O N

Cl

(37)

Lee et al. [63-65] from Green Cross Corp. reported some novel pyrazole-containing compounds as CB1 receptor inverse agonists/antagonists (38 -- 42) for the treatment of obesity and obesity-related metabolic disorders. Different heterocyclic substituents like 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole, tetrazole, triazole, pyrazole, oxazole, thiazole, isoxazole and isothiazole were attached to the third position of the pyrazole ring. Further, Lee et al. [66] disclosed novel diarylpyrazole 4-carboxamide derivatives as CB1 receptor antagonists having 1,3,4-oxadiazole (45) and 1,3,4-thiadiazole (46) groups attached to third position of the pyrazole ring. Compound (45) having pyridinylcarboxamide attached to the fourth position and oxadiazole ring to the third position of pyrazole ring showed the highest activity in the series (IC50 value = 0.00147 µM), whereas compounds (46) containing a cyclopropylcarboxamide at the fourth position of the pyrazole ring also exhibited good activity with an

imide and hydroxyamidine groups. Introduction of these polar groups at this position was useful for modulating the peripheral activity of CB1 receptors. The designed compounds were having reduced propensity to induce psychiatric and CNS side effects. Compounds (49 -- 51) having substituents like amide, imide and hydroxyamidine at fourth position showed IC50 values in the range of 0.5 -- 5 µM in the functional CB1 receptor assay. Further, attachment of 4-cyanobenzyl, 4-flurophenyl and piperidinyl groups with carboxmide attached to the third position of the pyrazole ring in compounds (52 -- 54) showed IC50 values less than 0.5 µM. In 2012, Receveur et al. [70,71] again reported some compounds (55 -- 59) as peripherally acting CB1 receptor antagonists. These compounds were having five-membered ring systems like oxadiazolinone, triazolinone, imidazolidinedione and succinimide attaching to the fourth position of the pyrazole ring. Compounds (55 -- 59) showed IC50 values of less than 0.5 µM.


7

M. K. Sharma et al.

N Cl

N Br

Cl

N N

N N

Me

N N N N Cl

N N N N

CF3

O

Cl

Cl

N N


Cl

(40) Cl

Cl

Me

Me

Me

N

N

N N

Me

N

Me

N N

Me Cl

Cl

Cl

(41)

O

Cl

N O N N Me

Cl

HN

Br

O

Cl (45)

(44) Br

N N

Me Me Cl Me

N N

CF3

Cl

N N CF3

S

Cl

(47)

(48)

NH2

NH2 Cl

O

N OH

O N N

N Me

H2N

Cl

HN

O N

Me

(46)

N N

N N

Me Me

S

Cl

Me O S O

SMe

O

O N N

Cl

N N

HN

O

N N

Cl

Me

Cl

N N

Me Me

Me

S

(43)

N

Me

Cl

N N

Me Me Me Cl

(42)

Cl

Cl

Cl

(39) Me

Cl

N N

S

Cl

(38) Cl

N N N N

Et N

HN

N N

Et

O

Et

HN

N Et

Me Cl

Cl

Cl

(49)

(50)

N OH

NH2

NH2 Cl

(51)

Cl

CN

O

Cl

HN

O N N

N N

N N

HN

HN

F

(53)

(52) N O N N

N R1

(55) R = Me

HN O O

(56) R =

Cl

(54)

CF3

H N

R

R1 = H

O

(57) R = N NH

O O

R2 = Me

N N

NH O

(55, 56)

O

HN N

Cl

Cl

R

Cl

O

O

Cl Cl

H2N

N

(58) R =

Cl

(57-59)

F

N H

SO2Me O NH

(59) R = HN

O

8




With the aim to develop peripherally acting CB1 receptor antagonists, McElroy et al. [72] from Jenrin Discovery endeavored to discover potentially effective and highly selective CB1 receptor antagonists having marginal or no CNS side effects including mood disorders. All these efforts were targeted to CB1 receptors in the peripheral tissues. It was speculated that the CB1 receptor antagonistic properties in the peripheral tissues could provide therapeutic agents having high safety. Ethyl group was introduced to the fourth position and other groups like ester, amide and piperidine to the carboxamide at third position of the pyrazole ring to get compounds (60 -- 62). Some other compounds (63 and 64) having methyl group at fourth position and substituted cyclohexyl ring at third position of the pyrazole ring were also reported. All these compounds exhibited CB1 receptor antagonistic activity with IC50 less than 10 µM. Cl

N N

N

(63 ) R =

HN R (64) R =

CO2Et

Cl

Cl

Cl

Cl

Cl (69)

In the same year, Makriyannis et al. [75] also reported neutral CB1 receptor antagonists having high selectivity toward peripheral CB1 receptors. Compound (70) with 2,4-dichlorophenyl group at first position, morpholine ring attached to the carboxamide at third position, hydroxymethyl at fourth position and cyanobutynylphenyl group at fifth position of the pyrazole ring showed a Ki value of 0.007 µM in [3H] CP55,940 competitive binding assay with a selectivity (CB1/CB2) ratio of 240. Only 0.6%/g of the compound (70) enters the brain 15 min after iv administration, whereas rimonabant gets 1.8%/g indicating that the designed

EtO2C O

N N

(68)

(60-62) Cl

O

N N

CO2Et

(62) R =

Cl

Me O

CONH2

(61) R = HN R

Me

Cl Me

Cl

O

Cl

Cl

CO2Et

(60) R = Et N N

third position of pyrazole ring exhibited very poor inhibition (0.02%) of CB1 receptor, whereas introduction of S-sec·butyl group in compound (66) showed 52% inhibition at 0.2 µM concentration. Almost equivalent activity was obtained for compound (67) having morpholine ring showing 53% inhibition of CB1 receptors at 1 µM concentration. Greig et al. [74] reported some 1,5-diaryl pyrazoles as neutral CB1 receptor antagonists. The amide linkage at third position of rimonabant was replaced by ketone functionality converting the compounds from inverse agonists/antagonists to neutral antagonists. Compounds (68 and 69) showed KD values of 0.0014 and 0.0023 µM, respectively, in [35S] GTPgS functional assay.

(63, 64)

Cl Cl

Me

Me (65) R =

Me

Me

O N N

O Me

HN

(66) R =

R Cl

N N

Me

Cl

Cl

HN N

O

Cl

(65, 66)

(67)

Xia et al. [73] from Janssen Pharmaceutica invented novel 5-vinylphenyl-1-phenylpyrazole derivatives. Compound (65) having S-cyclohexylethyl group attached to carboxamide at

compound (70) shows low penetration into the brain. All the reported compounds from the series were having Ki values between 0.0005 and 0.1 µM with CB1/CB2 selectivity ratio NC

NC HO

(71) R =

Me N N Cl

HN N

Cl

(70)


N

O

O N N

O Cl

Cl

HN R

(72) R =

O N

(71, 72)

9


M. K. Sharma et al.

of 5 -- 5000. Further, Makriyannis et al. [76] substituted methyl group to fourth position and piperidino group was attached to the carboxamide at third position to obtain compound (71) having a Ki value of 0.00035 µM with selectivity ratio ranging from 22 to 480 for CB1 receptors. In the same year, Makriyannis et al. [77-79] reported compound (72) in which piperidino ring of 71 was substituted by morpholino exhibiting a Ki value of 0.00089 µM with 100-fold selectivity for CB1 receptors over the CB2 receptors. Barth et al. [80] discovered novel sulfonamide derivatives as CB1 receptor antagonists. Efforts were made to introduce cyano, methoxy, hydroxyl, hydroxymethyl, amide and tetrazole moieties to the fourth position and aryl sulfonamide to the third position of the pyrazole ring. These compounds (73 -- 76) were claimed to have IC50 values less than 0.5 µM.

Imidazole derivatives A new class of CB1 receptor antagonists was developed by replacing the pyrazole ring of rimonabant with the imidazole ring. Lange et al. [83] invented 1,2,4,5-tetrasubstituted imidazole derivatives as selective CB1 receptor antagonists. It was observed that introduction of sulfur-containing groups at fifth position of the imidazole ring could offer compounds with CB1/CB2 ratio of more than 100. Compound (81) with methylsulfanyl group at fifth position of imidazole ring exhibited a Ki value of 0.005 µM and CB1/CB2 ratio of more than 200, whereas compound (82) having methylsulfonyl at the same position showed a Ki value of 0.012 µM with enhanced CB1/CB2 ratio of 638. Similar types of compounds were discovered by Green Cross Corp. where Lee et al. [84] patented novel imidazole-containing 2.4

Cl

O O

O HN S O R (74) R =

N N Cl

R′ = CN;

(73) R =

R′

CF3

F

R′ = CH2OH;

With the aim to minimize CNS-related side effects, Fulp et al. [81,82] from Research Triangle Institute, North Carolina (US), developed peripherally restricted CB1 receptor antagonists, which did not cross the blood--brain barrier (BBB). Generally, higher topological polar surface area (TPSA) corresponds to lower penetration into the CNS. TPSA of the compounds was enhanced by substitution of polar groups like sulfamide or sulfonamide, pyridine N-oxide and piperidine. Compound (77) having pyridine ring attached to the carboxamide groups at third position of the pyrazole ring exhibited a Ki value of 0.056 µM in radioligand displacement assay with high CB1 selectivity (CB1/ CB2 = 31). Compound (78) bearing a charged group like pyridine N-oxide was reportedly having a Ki value of 0.294 µM with CB1/CB2 value = 15. The sulfonamide derivative (79) with increased TPSA (i.e., 101) showed a Ki value of 0.036 µM. Higher potency and selectivity were obtained in the piperidino derivative (80) with a Ki value of 3.44 nM and CB1/CB2 ratio of 1600. Cl Me

Me

O

O N N Cl

HN

N N

N

O O S Me NH

Cl

HN

Cl

(7 7)

O N N

HN

(78)

Me O

(79)

10

N N

N

Cl O

Cl

N O

Cl

Me

N H

Me N

N HN N

Cl

CF3

Cl

R′ =

(76) R =

Cl

(73-76)

R′ =

(75) R =

(80)

NH2

compounds as CB1 receptor inverse agonists or antagonists. Their efforts were mainly focused to modify groups at fourth position of the imidazole ring by substituting oxadiazole, thiadiazole, oxazole and thiazole groups and implanting various alkyl/heteroalkyl groups at fifth position. Compound (83) having thiazole ring at fourth position and ethyl group at fifth position showed an IC50 value of 0.0105 µM. Replacement of thiazole ring with oxazole ring in compound (84) yielded an IC50 value of 0.00898 µM. Antagonistic activity was further enhanced by attaching thiadiazole moiety at fourth position and triazolylmethyl at fifth position in compound (85) giving an IC50 value of 0.00170 µM. The highest antagonistic activity in the series was exhibited by compound (86) in which oxadiazole ring was introduced at fourth position of the imidazole ring exhibiting an IC50 value of 0.00114 µM. Makriyannis et al. [85] discovered some novel selective and potent imidazole derivatives as CB1 receptor antagonist. Compound (87) having tetrazole ring substituted to the para position of the phenyl ring showed a poor Ki value of 5.762 µM. Replacement of tetrazole ring with iodo and 3-azidopropyne groups at the same position and methyl group at fifth position of the imidazole ring resulted into compounds (88 and 89) having much higher activity, i.e., Ki value of 0.0012 and 0.001 µM, respectively. Compound (89) showed a CB1/CB2 selectivity ratio of 82. The invented compounds were found to be CB1 antagonists showing Ki values in between 0.001 and 5.762 µM with selectivity ratio of 2 to about 452 for CB1 receptors.



Cl

Cl

Br

SMe O

N N Cl

N

N

HN N Cl

Cl

Cl

Cl

N N

O Me

Cl

Me Me

N

Cl

N N

N CF3

S

Cl

(84)

N

Cl

O

Cl

(85)

(86)

N3

I

HO

Me O

N N

N

Me

N

HN N

O

N

NH NH

N

N N

O Cl

Cl

Cl

Triazole derivatives Pyrazole ring of rimonabant was successfully displaced by various triazoles as the scaffold. Hou et al. [86] invented 1,2,3-triazole derivatives as CB1 receptor antagonists. An ester derivative (90) showed 90.3% inhibition at 10 µM and an IC50 value of 1.173 µM. Substitutions at second position of triazole ring were carried out and finally compound (91) having 4-fluorobenzyl group attached to the carboxamide at second position showed the highest activity with IC50 value of 0.0116 µM and good selectivity for CB1 over CB2 receptors. Lange et al. [87] invented 1H-1,2,4-triazole derivatives. Monoand di-substituted aryl groups with halogens at second and fourth positions and substituted carboxamido group at third position of the triazole ring resulted into compounds (92 and 93) having in vitro pA2 values of 7.2 and 8.2, respectively. Cl

Cl

(89)

Pyrazoline derivatives Novel 1,3,5-trisubstituted 4,5-dihydro-1H-pyrazole derivatives as CB1 receptor antagonists were reported by Lange et al. [88]. Carboxamide (94) and sulfonamidine (95) derivatives exhibited 98 and 79% inhibition at 10-6 M concentration in in vitro CB1 receptor antagonism. In yet another patent, Lange et al. [89,90] invented (5R)-1,5-diaryl-4,5dihydro-1H-pyrazole-3-sulfonamidine derivatives as CB1 receptor antagonists. A difluoropiperidinyl substituted compound (96) and a trifluoromethylpiperidinyl derivative (97) showed pA2 values of 8.8 and 9.5, respectively. The Risomer (96) was found to be 40 times more potent than its S-isomer. 2.6

N N

N N

HN N

N N

N N O

N

O C4H9

O Cl

Cl

N N Cl

O HN N

Cl

(95) O O N S R1 NH

H

Cl

N

O

N N

HN

Cl (92)

Cl

(94)

F

(91)

Cl

Me Cl

Cl

(90)

Cl N

Cl

NH

O N S O N NH

O

Cl

N

Cl

Cl

(88)

2.5

Cl

Me

Cl

(87)

Cl

CF3

N N N H

Cl

Me Me

N N

N

N N


Me

Cl

Cl

N

S

(83)

N N

N Br

N

N

N

(82)

Me

Cl

N

N

HN N

(81)

Br

Me

SO2Me O

(93)

N N Me Cl

F

(96) R1 =

N F

(97) R1 =

N

CF3

(96, 97)

Jenrin Discovery, West Chester, PA (US) has been involved in a long-standing research program for the development of Expert Opin. Ther. Patents (2015) 25(10)

11

M. K. Sharma et al.

CB1 receptor antagonists. The output of the research work related to pyrazoline-containing derivatives by McElroy et al. [91] proved beneficial for the designing of peripherally acting compounds. Novel sulfonamide- and carboxamidecontaining pyrazolines (98 and 99) were reportedly acting peripherally with reduced CNS exposure due to limited penetration into BBB. In another patent, McElroy et al. [92]

reported some compounds, which could preferentially target CB1 receptors in peripheral tissues such as adipose, liver, muscle, pancreas and GIT, while sparing CB1 receptors in the brain. Introduction of various ester groups at different positions of pyrazoline offered compounds (100 -- 102) exhibiting CB1 receptor antagonistic activity with IC50 of less than 10 µM. In the same year, McElroy et al. [93,94] discovered O OEt

NH2 Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Nyu Medical Center on 07/23/15 For personal use only.

O N S O

N N

O O S N Me H

HN

(98)

N

(99)

Cl

OEt

O Cl

Cl O N N

Cl

O

N N

N N

HN N

Cl

Cl

EtO

O O N S

N N

HN N Cl

Cl

O

(100)

N N

O

O

OEt

(102)

O O N S

O

HN Me

O

Cl

(101)

O

HN

N N

OEt

Cl

NH OEt

Cl

Cl

(103)

O O N S N N

(104)

N N O

O

N

O

O O N S

Cl

S

HN

HO

Cl

Cl

NH2

H2N

(105)

NH

NH2 O

Me Me

(106)

Cl O O N S

Cl

(108) R =

N N Me

R

NH

MeO

N N

NH2 O (107)

N S O O HN

(109) R =

NH2 Cl

(108, 109) O

Cl OH (110) R =

N S O N O N HN R Cl

12

H2NOC

Me OH

(111) R =

H2NOC

(110, 111) Expert Opin. Ther. Patents (2015) 25(10)

Me



Cl

some peripherally acting CB1 receptor antagonists to reduce or eliminate CNS side effects. The reported compounds (103,104) showed lowered CNS exposure with inability or limited ability of participation in active transport system. It was aimed to reduce centrally mediated adverse effects, which created potential problems with many antiobesity agents. In another patent, McElroy et al. [95] further reported novel pyrazoline derivatives having reduced CNS exposure due to their limited ability to penetrate the BBB with reduced centrally mediated side effects. A thiazole-containing compound (105) showed IC50 value in the range of 1 -- 10 µM. Compound (106) having sec-butyl carboxamide group at the same position showed IC50 value in between 0.1 and 1 µM, whereas compound (107) with ethyl carboxamide at this position exhibited an IC50 value of less than 0.1 µM. With the aim to find potent and highly selective peripherally acting CB1 receptor antagonists with less CNS adverse side effects, McElroy et al. [96-98] further invented novel diastereomeric pyrazoline derivatives. The synthesized compounds possessed asymmetric centers and geometric locants or both, and were isolated in optically pure or racemic forms. The R-enantiomer (108) exhibited an IC50 value of more than 1 µM, whereas its S-enantiomer (109) exhibited IC50 value in between 0.01 and 0.099 µM. Likewise, (2R’ , 3S’ , 4S)-isomer (110) showed IC50 value in between 0.1 and 0.5 µM, whereas the (2S’ , 3R’ , 4S)-isomer (111) offered an IC50 value less than 0.01 µM. Vela et al. [99,100] from Laboratorios Del Dr. Esteve, S.A. invented novel 4-methyl-4,5-dihydro-1H-pyrazole-3-carboxamide derivatives as neutral CB1 receptor antagonists, which acted either on CNS or peripheral nervous system or both. Neutral CB1 receptor antagonists are used for reducing appetite without inducing the CNS side effects. 2,6-Dimethylpiperidin-1-yl-containing S-isomer (112) showed an IC50 value of 0.00752 µM.

Me O Me N N Cl

HN

Cl

N Me

(112) 2.7

Imidazoline derivatives

Lange et al. [101,102] invented 1,2,4-trisubstituted imidazoline derivatives as CB1 receptor antagonists. Carboxamide or sulfonamide groups were attached at fourth position of the imidazoline ring. Compound (113) exhibited in vitro antagonistic activity with a pA2 value of 7.7. Cl O

N N Cl

HN

Cl (113)

2.8

Pyrrolidine derivatives

Research group at Eli Lilly and Co. has been actively engaged in exploring 1,5-diphenylpyrrolidin-2-one derivatives as CB1 receptor inverse agonists for the treatment of obesity. Schaus et al. [103-105] reported compounds having phenyl groups at first and fifth positions of the pyrolidine ring substituted with grouping like chloro, cyano, trifluoromethyl and trifluoromethoxy. Some of the compounds were reported to have pyrimidine ring with cyclopropyl (114) trifluoromethyl (115) and cyano groups attached to the second position of the pyrimidine ring. Compounds (114 and 115) exhibited antagonistic activity with Kb values of 0.000644 and 0.00083 µM, respectively. These compounds were highly selective toward CB1 receptors having CB1/CB2 ratio of more than 1000. Coffey et al. [106,107] from the same company further extended the 1,5-diphenylpyrrolidin-2-one series. The F3CO

F3C

O

O N

N

NH

NH Me

N

Me

Me N

N Me N

CF3

OCF3 (114)

(115)

R O

F3CO O N R

N

(116) R =

NH

NH CF3

Me Me

CF3

Me

N

Me

(117) R =

O

F F CHF2

(116, 117)

N

(118) R = CF3 (119) R = Cl

(118, 119)


13

M. K. Sharma et al.

(3S, 5S)-isomer (116) showed Kb value of 0.107 µM while the (3S, 5R) form (117) exhibited a Kb value of 0.0727 µM, indicating that the 5R-isomer was more potent than the 5S form. Further, the (3R, 5R) form (118) showed the highest activity with a Kb value of 0.00071 µM with CB1/CB2 ratio of more than 9000. Replacement of trifluoromethyl group with chloro group at fourth position of the phenyl ring resulted Cl

exhibited a Ki value equal to or less than 0.8 µM, whereas removal of the carbonyl group at third position as was the case with compound (125) enhanced the activity with a Ki value equal to or less than 0.055 µM. Further, introduction of pyridine with sulfonamide group at second position of morpholine ring in compound (126) showed a Ki value equal to or less than 0.025 µM. Cl

O O

N O


O Cl

Me Me Me

Cl

Cl

Me

NH

O

N

Me Me Me

Cl

O O

N

Me

(120)

(121)

O HN

O

O N

Cl

HN

NH Me Me

Me

Cl

N Cl

(122)

2.10

O

Me N Me Me Me

Cl (123)

Morpholine derivatives

Scott et al. [111,112] from Schering Corp. invented a novel class of diaryl morpholine derivatives as CB1 receptor antagonists. Compound (124) having carbonyl group at third position and t-butyl ester substituent at second position of morpholine ring 14

Me Me Me

Cl

N HN

N

Cl

N

O

O

N

S O O

O

HO

Cl

H N

Piperazine derivatives A novel series of diaryl piperazine derivatives as CB1 receptor antagonists was discovered by Demong et al. [113] from Schering Corp. Modifications were carried out mainly at first and fourth positions of the piperazine ring. Compound (127) with 2,4-dichlorophenyl substituent at fourth position and 2-methoxyphenylmethanone at first position of piperazine ring and the other compound (128) with 2-hydroxyethoxy group at para position of the phenyl ring attached to the fourth position of piperazine ring and a benzamide group attached to propanyl side chain at first position of the piperazine ring were claimed to possess potent CB1 receptor antagonistic activity with selectivity for CB1 over CB2 receptors. Similar type of compounds was reported by

Pyridine derivatives Merck Sharp & Dohme Corp. patented novel furopyridine derivatives as CB1 receptor antagonists [108]. Clements et al. from the company introduced oxadiazole and pyrazole in the para position of the phenyl ring in compounds (120 and 121) having IC50 values of 0.0004 and 0.001 µM, respectively. In another patent, Debenham et al. [109,110] from Merck & Co., Inc. invented substituted pyrano[2,3-b]pyridine derivatives. Compound (122) with pyrano[2,3-b]pyridine ring showed the highest IC50 value of 0.001 µM and compound (123) exhibited IC50 value of 0.002 µM.

N

(126) R =

Me Me Me

2.11

2.9

O

Cl (125, 126)

(124)

Cl

O

O Cl

into compound (119) having Kb value of 0.00091 µM with enhanced CB1/CB2 ratio to more than 15000.

R

N

(125) R =

Gilbert et al. [114,115] from Intervet Inc, where first and fourth positions of the piperazine ring were substituted with different groups and maintaining R-configuration at third position as shown in compounds (129 and 130) as CB1 receptor antagonists.



O

between 0.01 and 0.1 µM, whereas the acid hydrazides (133 and 134) showed IC50 values less than 0.01 µM.

OMe

N

O

N Cl

Cl

N N

Cl

HN

N

Me O

N N

O

O

(127)

HN

Cl

N

HN S O O

NH2 Cl

N

O

(131)

Cl

N N

Cl

(128)


N N

OH HO Me

O Me

Me

(130, 3R)

2.12

Pyrimidine derivatives

Moritani et al. [116,117] from Tanabe Seiyaku Co. Ltd. reported novel pyrazolo[1,5-a]pyrimidine derivatives as centrally acting CB1 receptor antagonists. Carboxamide derivatives like compounds (131 and 132) exhibited IC50 values in

Cl

N N N Cl

HN Me Cl

(135)

Cl O S O Cl

(137)

O O S NH2 N O N N HN N N Me

Cl

Cl

Cl (138)

F3C

(134)

O CONH2 O S NH N O N HN N

(136)

O O S NH2 N O N HN N N

Cl

Me

Tanimoto et al. [118] from Mitsubishi Tanabe Pharma Corp. patented pyrazolo[1,5-a]pyrimidines as CB1 receptor antagonists. Compound (135) with a cyclohexyl group attached to the carboxamide at third position showed IC50 value in between 0.01 and 0.1 µM. Introduction of methylsulfamoyl group at second position in compound (136) and acetamide group attached with sulfamoyl group at second position in compound (137) exhibited IC50 values in between 0.01 and 0.1 µM. Sulfamoyl group only at second position enhanced the activity as was the case with compounds (138 and 139), which showed IC50 values less than 0.01 µM. In the same sequence [119-121], replacement of the cyclohexyl group of compound (135) by 1,1-dioxotetrahydrothiopyran in compound (140) showed same degree of activity but resulted into more than 500 times higher CB1 receptor

O O S NHMe N O N HN N

Cl

O

HN N

Cl

(133)

N N

N

N Cl

NH2

(129, 3R)

MeO

O

N

Cl

N

Me

CN

F

N N

O

N

N O

HN N

CF3

Cl

O N

Cl

HO

(132)

HO Me

N HO

Cl

(139)

O(CH2)2OH

Cl

N N

N N

O O N

HN

CN (140)

O Me

NH2 N S O O

HN S O O

Cl


(141)

15


M. K. Sharma et al.

R Cl

R

selectivity over CB2. Introduction of 2-hydroxyethoxy group at second position and 1,1-dioxotetrahydrothiophene ring at third position in compound (141) exhibited an IC50 value of less than 0.01 µM and CB1/CB2 selectivity ratio of more than 500. Debenham et al. [122] from Merck and Co. Inc. reported some novel pyridopyrimidine derivatives. Compound (142) having an amine group at fourth position of the pyrimidine ring exhibited an IC50 value of 0.011 µM, whereas replacement of the amine by 4-fluorophenyl group in compound (143) exhibited better antagonism with reduced IC50 value to 0.0006 µM. Debenham et al. [123] in another patent reported novel pyridotriazolopyrimidine derivatives. Compound (144) with oxadiazole ring attached to the fourth position of the phenyl ring exhibited IC50 value of 0.011 µM. Replacement of the oxadiazole ring with Cl in

N

(147)

N

N

R1 O

R2

O N

N

(148)

Cl

C2H5

R1

Cl

R2

(149)

(147-149)

OCH2CO2C2H5

O

C2H5

NH2

O N H

OMe O O

C2H5

NH2

Maitra et al. [126] invented novel peripherally restricted diphenyl purine derivatives that did not cross the BBB and thus minimized CNS-related side effects. Compound (150) exhibited a Ki value of 0.355 µM with CB1/CB2 ratio of 30.2. Further modifications were carried out whereby a cyclopentyl group was attached to the piperidine carboxamide at fourth position of the purine ring in compound (151) showing a Ki value of 0.00154 µM and CB1/ CB2 ratio of 39. Cyclohexylmethyl in place of cyclopentyl in compound (152) showed a Ki value of 0.00193 µM with enhanced CB1/CB2 ratio of 1223. Compounds (153 Cl N N

N N

NH S NH2 O O

HN

Cl

(150)

Cl N N

N

(151) R =

(153) R =

(152) R =

(154) R =

N

N

O

Cl

O

Me Me

HN R

(151-154)

compound (145) enhanced the activity (IC50 value of 0.002 µM). Introduction of cyano group at fourth position of the phenyl ring in compound (146) showed the highest activity (IC50 value of 0.001 µM). Cl

R1 N N

R

(142) R = Cl, R1 = NH2 Me Me Me

N

Cl

(143) R = H, R1 = 4-Fluorophenyl

O N NH

R1

N

Cl

(144) R =

Me Me Me

N

R1 = H

N

O

N N

Azulene derivatives Xia et al. [127] patented a series of novel tetrahydro1H-1,2,6-triazaazulenes as cannabinoid modulators. Compounds (155 and 156) exhibited 39 and 52% inhibitions at a test concentration of 0.2 µM. 2.14

(142, 143) R

and 154) were studied to determine drug penetration into CNS at 10 mg/kg oral dose in SD rats. Brain and plasma samples were collected at 1, 2, 4 and 24 h post-dose. Compound (153) showed brain-to-plasma ratio ranging from 0.14 to 0.46, whereas it ranged from 0.03 to 0.13 in compound (154) indicating minimal to almost no penetration into the CNS.

(145) R = Cl

R1 = H

(146) R = Cl

R1 = CN

Cl

N

(144-146)

2.13

N

O

O

(155) R =

OMe

HN N

Purine derivatives

McElroy et al. [124,125] invented novel purine derivatives (147 -- 149) as CB1 receptor blockers. These compounds exhibited CB1 receptor antagonistic activity equal to or less than 10 µM. 16

Cl

F


N R

(155, 156)

(156) R =

Boc


2.15

Davidson et al. [131] discovered azetidine-1-carboxamide derivatives as CB1 receptor antagonists. Compound (161) exhibited a Ki value of 0.08 µM. More electronegative trifluoromethyl group at second position of phenyl ring as well as fluoro and bromo groups at second and fourth positions of the other phenyl ring, respectively, led to a potent compound (162) having a Ki value of 0.0013 µM. R-form of compound (163) exhibited a Ki value of 0.0006 µM.

Azetidine derivatives

Altisen et al. [128] discovered novel substituted azetidine compounds. Compound (157) with 4-fluorophenylsulfonamide group showed 59% inhibition at 10-6 M of [3H]-CP55940 at CB1 receptor. The compound (157) showed good selectivity toward CB1 receptors with a Ki value of 0.264 µM. Cl

Cl N

Br

NH O S O Me

O

Cl


F

O HN

F

(157)

Baker et al. [129,130] discovered novel heterocyclic substituted 3-alkyl azetidine derivatives as centrally acting selective CB1 receptor antagonists. Compounds (158 -- 160) with oxadiazolidinone/oxadiazole attached to the different positions exhibited IC50 values less than 1 µM with 100-fold selectivity toward CB1 receptors. N

O

O

(163)

McElroy et al. [132,133] invented novel substituted aminoazetidines as CB1 receptor antagonists. Compounds were designed with the aim to target the peripheral CB1 receptors preferentially to minimize or eliminate CNS side effects. Different substituents at the tertiary nitrogen as in compounds (164 -- 167) and second position of the azetidine ring as in compounds (168 -- 171) were synthesized. Some charged molecules such as compound (172) were also prepared. The quaternary nitrogen prevented its entry into the BBB. This type of compounds could also be used for the treatment of obesity without concern of CNS adverse effects. Each class of these compounds (164 -- 172) exhibited antagonistic activity at less than 10 µM concentrations. Auger et al. [134] from Sanofi-Aventis invented some azetidine derivatives. Compound (173) having propylhydroxy group attached to the carboxamide in S-disposition exhibited

N CN NC

F (159)

(158)

CN

F F

N F Me Me O O

N N H

(160) Cl

F

O

N

O OO S

O

F ( 164) R =

OEt

N H

(166) R =

O

OEt

N H

O

N R

(165) R =

O O O S

(164-167)

Cl

Me Me Me

N HN

F Me Me Cl

CF3 (162)

O

Me Me F

O

N

HN

CF3

N NH

Me Me Me

N

(161)

O

F

O

Cl

NH2

N CN

Cl

O

Me Me Me

N

Cl

F

Me N H

OH

O

OO S

(167) R =

O

(168) R = COOEt

Cl

OH

N H F

F

F

(169) R = CHCOOEt N

N R

Cl

O S Me O

N

(170) R = CH2COOEt (171) R = CH(OH)COOEt

(168-171) Expert Opin. Ther. Patents (2015) 25(10)

Me Cl

N O S Me O (172)

17

M. K. Sharma et al.

an IC50 value of 0.016 µM while an additional hydroxymethyl group at the same position in compound (174) exhibited the highest activity with an IC50 value of 0.006 µM.

Cl

Cl

Cl O N

MeO

Me

O S

N N

OH

OH CF3


Me

(173)

Cl O Me O S N

O

N HN

OH

N N

EtO

CH2OH CH2OH

F

F (178)

(177)

Brown et al. [138] invented benzimidazole derivatives as CB1 receptor antagonists. Compound (179) exhibited a Ki value of 0.02379 µM. Introduction of difluoro group at fourth position of cyclohexylmethyl group at first position of benzimidazole in compound (180) enhanced the affinity with Ki value of 0.01917 µM. All of the reported compounds showed Ki values in the range of 0.016 -- 3.570 µM. O

Me

N

N Cl

Me N

O

N HN

Cl

N

N

N

(174)

O

N

Me Me Me

(179) R = H; R1 = H

NH

Miscellaneous compounds Jaehne et al. [135] reported imidazolidine-2,4-dione derivatives. Compound (175) with methylsulfanyl group at third position of phenyl ring showed a Ki value of 0.217 µM, whereas cyano group at fourth position and trifluoromethyl at third position in compound (176) showed a Ki value of 0.002 µM. 2.16

O

Me Me

MeS N

N O

(175)

O

R1

(179, 180)

Fletcher et al. [139] invented novel sulfonylated piperazine derivatives as CB1 receptor antagonists. Naphthylsulfonylcontaining compounds (181 and 182) showed IC50 values of 3.791 and 3.188 µM, respectively. 3,5-Bis(trifluoromethyl) phenyl-containing compound (183) showed equally poor activity with IC50 value of 3.221 µM. Compound (184) having acetyl group at third position of phenyl ring attached to the sulfonamide showed an IC50 value of 0.00607 µM, and cyclopropyl at the same position in compound (185) showed an enhanced activity with IC50 value of 0.00124 µM. O S N O

Me Me

N NC

(180) R = F; R1 = F R

N

O S N O

O N N

(181)

O

(182)

F3C

F3C

O N

O S N O

(176)

O N

F3C

With the aim to develop safer CB1 receptor inhibitors targeting exclusively CB1 receptors present in the peripheral tissues, Shin et al. [136,137] from Amorepacific Corp. reported novel pyrazolo[1,5-a]pyrimidine derivatives. Compounds were chemically modified in such a way that they did not cross the BBB and distributed only in peripheral tissues. Compounds (177 and 178) containing a pyrrolidine or methylaminoethanol group attached to the fifth position of pyrazolo[1,5-a]pyrimidine scaffold showed IC50 values of 0.004 and 0.007 µM, respectively. 18

(183) F3C

O

O

S N O

(184) R = CO2Me

N

R

CF3

(185) R = Cyclopropyl

(184, 185)

A novel class of ‘N-(arylalkyl)-1H-indole-2-sulfonic acid amides’ has been reported by Greig et al. [140]. Compound (186) showed an IC50 value of 0.4 µM. Both of the methoxyl groups in 186 were replaced with hydrogen and



4-fluorophenyl, respectively, resulting into compound (187) having an IC50 value of 0.001 µM. O S O HN

R N H

(186) R = OMe; R1 = OMe (187) R = H;

F

R1

(186, 187)


=

R1

Prather et al. [141] designed neutral CB1 receptor antagonists with the aim to retain beneficial properties of rimonabant and getting rid of the adverse effects. Compound (188), a dual-acting CB1 receptor antagonists/CB2 agonist, was used to achieve the desired goal with improved druglike properties. Molecular dissection approach was used to optimize the compound (188). Methoxy group was attached at seventh position of the indole ring and carbonyl group was reduced in compound (189), while naphthalene ring was directly attached to the indole ring in compound (190) exhibiting Ki values of 0.0154 and 0.0372 µM, respectively. These compounds (189 and 190) could be used as potential leads for further modifications. R

O

N OMe

N

Me (188)

Me

(189) R =

(189, 190)

(190) R =

Piazza et al. [142] invented some steroidal CB1 receptor antagonists. Introduction of fluorine atom at third position and methyl group at C-17 position generated 3-fluoro-17amethylpregnenolone. It was observed that 17a-methylpregnenolone (192) was more effective than pregnenolone (191), 3-fluoropregenolone and 3-fluoro-17a-methylpregnenolone in inhibiting the effect of CB1 receptor activation. 17aMethylpregnenolone was able to decrease significantly the enhanced food intake induced by THC in rats. Compounds (192 -- 194) showed ‡100% inhibition of THC-induced food intake by CB1 receptor antagonism. O Me Me

O

Me Me

Me Me

H

Me

H HO

HO (192)

(191)

O Me

O

Me

Me Me

Me F

F (193)

Me Me

(194)

3.

Expert opinion

The role of CB1 receptors in obesity has already been well defined. CB1 receptor antagonism is considered as an attractive and promising strategy for the treatment of obesity. Many new classes of CB1 receptor antagonists have been invented with interesting results. In this article, the authors have reviewed the patents that have been published in this field of medicinal chemistry since 2007 onward. Currently, researchers are focusing mainly on designing of peripherally acting CB1 receptor antagonists so that CNS side effects could be eliminated. Peripherally restricted compounds are devoid of CNS side effects due to their inability to penetrate into the brain. A molecule can easily penetrate BBB if the PSA is less than 60 A˚2. Thus, efforts have been made to increase the PSA and decrease the lipophilicity of the designed compounds so that these compounds could remain located peripherally. This can be achieved by introduction of polar groups in the lead molecules. A compound is considered to be peripherally selective if it showed < 10% brain penetration. Along with this approach, development of neutral antagonists, allosteric antagonists, inverse agonists and charged compounds has also been reported for making them safer drugs. All these efforts have ultimately led to the development of a large number of peripherally acting CB1 receptor antagonists. In peripherally acting compounds, CB1 inverse agonists may possess distinct advantages over neutral antagonists particularly for weight reduction. Promising compounds have been reported as peripherally acting CB1 receptor antagonists having different chemical scaffolds such as thiophene, pyrrole, pyrazole, pyrazoline, purine, azetidine and pyrazolo[1,5-a]pyrimide. Encouraging reports have appeared for compounds with low penetration into the brain [compounds having thiophene (5) and pyrrole (7) ring systems] as compared to rimonabant. The pyrazole derivative (80) showed high potency (Ki = 3.44 nM) and selectivity (CB1/CB2 value = 1600) with peripheral activity. A novel diastereomeric pyrazoline derivative (111) has also been claimed for its peripheral activity with IC50 value of less than 10 nM. A purine derivative (154) showed brain-toplasma ratio ranging from 0.03 to 0.13 in 1 -- 24 h at 10 mg/kg oral dose. An azetidine derivative (164) has also been claimed for the treatment of obesity without major concerns of CNS side effects having good antagonistic property. A pyrazolo[1,5-a]pyrimide derivative (177) has also been reported for peripheral antagonistic activity. These kinds of peripheral compounds have shown their potential to address the problem of obesity in a unique and specific way, which makes an enticing approach for the designing of safer CB1 receptor antagonists. Neutral CB1 receptor antagonists have been reported with minimum side effects. Introduction of cyanobutynylphenyl group at the fifth position and morpholine ring attached to the carboxamide at third position of pyrazole in compound


19


M. K. Sharma et al.

(70) has been reported with a Ki value of 0.007 µM with good CB1 selectivity (CB1/CB2 = 240). Interestingly, it is reported that only 0.6%/g of the compound (70) penetrated into the brain after 15 min after iv administration, indicating that this type of compounds can act as lead molecules for the designing of better CB1 receptor antagonists acting peripherally. Some charged compounds have also been reported as these would not cross the BBB as is the case with compound (78) having Ki value of 0.294 µM and some degree of selectivity toward CB1 receptors (CB1/CB2 = 15). Designing of charged compounds might prove beneficial for obtaining lead molecules, which could be further optimized as a drug for the treatment of obesity. Some Pharma companies have been actively engaged in the development and optimization of peripherally active selective CB1 receptor antagonists. An advanced research program of Jenrin Discovery is working on peripherally selective CB1 receptor antagonists, which would block CB1 receptors in peripheral tissues such as liver, muscle, adipose tissue, pancreas and GI tract. More than 800 molecules comprising three distinct chemical scaffolds have been designed and synthesized resulting into identification of multiple lead molecules. JD-5006 [143], a lead molecule, is currently being advanced toward an IND filing, and a number of backup candidates are also being identified, which could reduce body weight, fatty liver and serum levels of insulin and triglycerides [144]. MAKScientific is also actively engaged in the field of endocannabinoid research. AM6545 [145], an advanced drug candidate acting as a peripherally restricted CB1 receptor antagonist, is now in the preclinical stage [146]. It is suggested that AM6545 will have less neuropsychiatric side effects in humans. Further development of compounds of this class may be beneficial for the pharmacotherapy of this metabolic Bibliography

disorder. Another company 7TM Pharma [147] has also identified compound TM38837 [148], a second-generation CB1 receptor antagonist that acts peripherally [149] and has the potential to treat several metabolic disorders without CNS side effects. In 2010, the company announced that they have successfully conducted and completed Phase I clinical trials of compound TM38837 for the treatment of obesity and related metabolic disorders [147] and this type of compound should be further developed. With these efforts, it has become clear that there is a continuous and sustained progress in the development of safer CB1 receptor antagonists. Our group is also active on the development of safer selective peripherally acting CB1 receptor antagonists [150]. It is a matter of time that some novel peripherally acting CB1 receptor antagonists will be introduced in clinical practice as antiobesity agents having excellent potency and selectivity toward peripheral CB1 receptors for making them safe without involvement of CNS actions.

Acknowledgments MK Sharma is thankful to University Grants Commission, New Delhi, for awarding Junior Research Fellowships (JRF) under the RFSMS-BSR programme [No.F. 7-129/ 2007 (BSR)].

Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Affiliation Mayank Kumar Sharma, Prashant R Murumkar, Mahesh A Barmade, Rajani Giridhar & Mange Ram Yadav† † Author for correspondence The M. S. University of Baroda, Pharmacy Department, Faculty of Technology and Engineering, KalabhavanVadodara -- 390 001, India E-mail: [email protected]

Notice of correction Please note that changes were made in Table 1 and Reference 150 after initial online publication of this article (10th July 2015).

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