Therapeutic applications of lipoic acid: a patent review (2011 - 2014).

Review

Therapeutic applications of lipoic acid: a patent review (2011 -- 2014)

Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Dokuz Eylul Univ. on 11/05/14 For personal use only.

Maria Koufaki 1.

Introduction

2.

Patent applications related to LA and its derivatives

3.

Conclusion

4.

Expert opinion

Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece

Introduction: Lipoic acid (LA), a naturally occurring 1,2-dithiolane analog that plays an essential role in mitochondrial bioenergetic reactions, has gained unprecedented attention as nutritional supplement and as therapeutic agent. Moreover, LA conjugates with other pharmacophores represent a promising approach toward the development of multifunctional drugs. Areas covered: The reviewed patent applications from January 2011 to April 2014 include combinations of LA with other bioactive compounds as well as LA conjugates for the treatment of a wide range of clinical conditions. Additionally, some patents disclose methods to overcome the stability problems of LA. Expert opinion: LA is currently in clinical use for the treatment of diabetic neuropathy, while small clinical trials using combinations of LA with known bioactive agents have been undertaken. The use of the LA is hampered by its instability and its rapid metabolism. Thus, formulations containing LA, in a form ensuring its stability and improving its bioavailability, can have important applications as medicines, nutritional supplements or cosmeceuticals. LA hybrids with other pharmacophores endowed with various activities, possess an enormous potential to promote human health and have been the subject of numerous publications and patent applications. Nevertheless, reliable in vivo data and clinical trials are necessary to prove these beneficial effects. Keywords: cancer, diabetes, inflammation, lipoic acid, lipoic acid conjugates, neurodegenerative diseases, nutraceuticals, pain Expert Opin. Ther. Patents (2014) 24(9):993-1005

1.

Introduction

R-a-Lipoic acid (LA) is a natural product first isolated in 1951 by L. Reed from beef liver and ever since it has been the subject of numerous studies owing to its potential to intervene in various therapeutically interesting pathways [1,2]. LA is synthesized in vivo and it is covalently bound to a lysine residue. It is a cofactor for mitochondrial enzymes pyruvate dehydrogenase and a-ketoglutarate dehydrogenase and plays an important role in mitochondrial energy metabolism. Specifically, LA transfers the acetyl group formed by oxidative decarboxylation of pyruvic acid on Coenzyme A. NAD+ is the oxidizing agent and the reaction produces an equivalent of NADH in mitochondria, initiating Krebs cycle reactions. Only trace amounts are available from dietary sources. Exogenously supplied LA is transported to tissues and reduced to dihydrolipoic acid (DHLA) (Figure 1). LA and DHLA are a unique pair of antioxidants that express their activity in both hydrophilic and lipophilic environments. Specifically LA and DHLA can exert antioxidant effects by quenching reactive oxygen species (ROS), sparing the antioxidant vitamins C and E, inhibiting lipid peroxidation, chelating transition metal ions and increasing intracellular glutathione levels via activation of the redox-sensitive transcription factor, Nrf2 [3-7]. Because of its unique characteristics, LA is likely to 10.1517/13543776.2014.937425 © 2014 Informa UK, Ltd. ISSN 1354-3776, e-ISSN 1744-7674 All rights reserved: reproduction in whole or in part not permitted

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The majority of the reviewed patent applications are related to the use of LA compositions and conjugates for the prevention and/or treatment of inflammatory, neurodegenerative diseases as well as cancer, diabetes and pain. Several patent applications pertain to nutrient compositions containing LA and other bioactive molecules. The resulting medications were more effective than the individual components. Three patent applications report the administration of LA compositions to humans. Conversion of LA to its salts with various amines or use of basic solutions containing LA are claimed as efficient methods to overcome its stability problems and achieve better bioavailability. Although the synthesis of LA conjugates with other pharmacophores is not a new approach, recent inventions claim various therapeutic applications of LA hybrid molecules. However, few in vivo data are included in the reviewed patents.

and skin-lightening products, in which cosmetic industry has a major commercial interest [51-53]. Finally, LA has received great attention in recent years in the area of gold surfaces functionalization. LA capped gold nanoparticles (AuNPs) have proven to be an interesting alternative for the direct colorimetric detection of nerve agents [54], reduced glutathione [55] as well as the reverse transcriptase of the HIV type-1 (HIV-1 RT) in serum [56]. Moreover, LA conjugates with derivatized amine and amino acids attached to AuNPs, were the first example of enzyme activation, specifically carbonic anhydrase, with nanoparticles [57]. Besides the large number of publications, recent patent applications disclose the preparation of LA combinations, the synthesis of conjugates and their uses. This review summarizes patents related to LA and published from 2011 to 2014.

Patent applications related to LA and its derivatives

2.

This box summarizes key points contained in the article.

O

O

OH

OH S

S

a-lipoic acid (LA)

SH

SH

Dihydrolipoic acid (DHLA)

Figure 1. Chemical structures of LA and dihydrolipoic acid.

have therapeutic value in a wide range of clinical conditions related to oxidative stress [8-12]. The remarkable antioxidant profile of LA, along with the fact that it is a safe compound, sold over the counter as a dietary supplement [13], has attracted an unprecedented interest of the scientific community and led to an impressive number of reports on its biological properties. In parallel, several research groups have focused on the development of synthetic approaches required for efficient production of LA [14-20]. It should be noted that LA reportedly exerts most of its effects at high micromolar concentrations and has a very rapid metabolism. Amides or esters of LA exhibit higher biological activity than the parent compound, thus it is not surprising that LA has been extensively used for the synthesis of diverse conjugates with other pharmacophores. The last 15 years several research groups, reported the design and synthesis of LA-containing hybrid molecules [21,22] possessing antioxidant activity hyphenated with a wide variety of other activities such as cardioprotective [23-26], neuroprotective [27-38], anti-inflammatory [39-42], antidiabetic [43,44] and anticancer activity [45-50]. Furthermore, LA and its conjugates can be used in the preparation of anti-wrinkle, anti-ageing 994

There is evidence that LA has therapeutic value in lowering glucose levels in diabetic conditions. LA has been applied in clinical diabetic polyneuropathy, a pathologic condition associated with increased oxidative stress [58-61]. LA supplementation has multiple beneficial effects on the decline in mitochondrial function and on oxidative stress associated with disease and ageing. However, appropriate plasma levels need to be achieved to ensure maximum therapeutic benefit. The use of the LA as drug or food supplement is hampered by its rapid metabolism (man plasma half live of 30 min and bioavailability after oral administration of 30%) and its stability problems since it is known that LA can polymerize. Its degradation in the presence of light was characterized by a physical change in the compound and a shift in the ultraviolet spectrum. The polymerization of LA occurs via opening of the strained dithiolane ring, resulting in a diradical, followed by propagation through intermolecular disulfide bond formation [62]. Moreover, LA is an ideal chemical moiety to be covalently bound on various bioactive molecules creating new agents against complex diseases, in which free radicals play an important role. Therefore, the design and synthesis of LA-containing hybrid molecules have been the subject of intensive research in the last 15 years. In general, the resulting conjugates exerted enhanced bioactivity compared to parent compounds and represent a promising approach toward the development of multifunctional drugs. The patents that are reviewed in the present report are focused on the above-cited issues. Compositions, formulations containing LA Combinations of bioactive compounds have therapeutic benefits, including the reduction of the amount of each component necessary for therapeutic activity and of side effects. 2.1

Expert Opin. Ther. Patents (2014) 24(9)


Therapeutic applications of lipoic acid

LA and N-acetyl cysteine (NAC) are ingredients of various compositions claimed in the reviewed patents. Low-dose CNS stimulant containing methylphenidate as CNS medication altogether with specific nutrients acetyl L-carnitine, L-tyrosine, NAC and LA are disclosed in the invention [63] for the treatment of chronic fatigue syndrome. No prescription drugs have been developed specifically for this multifactorial condition, so far. The examples describe a 12-week clinical trial in 15 patients. Patients responded significantly with a mean fatigue symptom reduction of 41 -- 54% depending on the instrument used to assess change in fatigue. However, when LA and NAC were combined in a nutritional supplement (NS) the LA concentrations decreased up to 50% probably because LA reacts with NAC as inventors of the application [64] state. This invention describes NS containing LA and a sulfur containing compound, such NAC which increases the level of cellular glutathione (GSH). The supplement can contain any form of LA and its derivatives. The invention is based on the individual abilities of LA and NAC to increase GSH. The novelty lies in the development of a single delivery vehicle that limits the contact between the two ingredients. The examples include the preparation of bilayer tablets containing LA and NAC to increase stability of the ingredients for a period of 6 months. The same inventors incorporated the US disclosure cited above in the application [65], which claims the use of the NS containing LA and sulfur compounds. The NS were administered to healthy individuals and blood GSH levels, blood glutathione S-transferase (GST) activity, serum antioxidant reserve (SAR) and plasma vitamin C levels were determined for a total of 28 days. The results showed that these NS taken regularly, can increase the levels of GSH, GST activity and antioxidant protection in the blood. A nutrient composition, including LA, NAC and acetyl L-carnitine, is claimed in the invention [66], which is a continuation of previous applications. The NSs of the disclosure include an optimal combination of an effective amount of at least one antioxidant vitamin (vitamin C, bioflavonoid complex, vitamin E, vitamin B6 or b-carotene), at least one mineral antioxidant (zinc or selenium) and a highly saturable amount of at least three high potency antioxidants (LA, acetyl L-carnitine, NAC, coenzyme Q10 or GSH). The first example showed the effect of NS in patients with peripheral neuropathy induced by stavudine or didanosine antiviral therapy. A total 40 patients were enrolled in the 1:1 randomized patient to placebo study. The nutrient packet administered twice daily included: multivitamin and multimineral composition, vitamin B6 130 mg, acetyl L-carnitine 500 mg, LA 200 mg and NAC 600 mg for 12 weeks. Patients taking the NS experienced a slight decline of copies in HIV RNA viral load compared to placebo group. Moreover, the NS-treated group showed statistically significant rise in CD4 counts over 12 weeks. LA and honokiol are ingredients of various NS. Honokiol is a phenolic compound possessing neurotrophic activity,

obtained from Magnolia Officinalis. The novelty claimed in the application [67] pertains to the higher amount of honokiol and the potential of the composition to treat neuropathies. The effect of various concentrations of a mixture of LA and honokiol on a primary cell culture of rat cortical neurons after 7 days (length of neuritis at the microscopic level) was evaluated. Best results were obtained with LA 95.5% -- honokiol 4.5% and LA 91% -- honokiol 9%. LA stability is a major issue and methods to improve it are disclosed in recent patent applications. Thus, to overcome stability problems, LA can be converted to salts with nitrogen organic bases. Since prior art exists, the inventors of [68], claim as novelty the specific examples. Examples include salts of RLA with trometamol, cystamine, diazabicyclo[2,2,2] octane, piperazine, formulations containing LA and the prepared LA salts, dissolution profile of organic base R-LA tablets and stability assessment at 40 C. LA salt with piperazine is also disclosed in the application [69]. This invention pertains to a pharmaceutical composition containing LA salt with piperazine and the antidiabetic drug glimepiride for the treatment of type 2 diabetes mellitus. LA was converted to its crystalline piperazine salt that had good thermal and moisture stability and water solubility. Examples include preparation of racemic and R-LA piperazine salt X-ray structures, tablet formulations and in vitro glucose uptake tests. The claimed medication was more effective in lowering blood glucose levels and increasing glucose uptake in cells than the individual components LA and glimepiride, and has pharmacological efficacy at a concentration of 1 and 10 µg/ml. The invention [70] claims the preparation of a solution of LA in order to overcome stability problems of LA and achieve better bioavailability. Specifically, the examples include the preparation of solutions of R-LA in variable volumes of propylene glycol and varying pH values, concluding that pH 7.0 -- 9.5 was prerequisite for optimum stability while pH inferior to 5 resulted to an unpleasant smell. Best results were obtained with an aqueous solution of 30% propylene glycol, 60 mg/mL of LA, pH 8.5, while further analysis of this solution in different temperatures revealed significantly high values of the titer of LA even after 9 months after the preparation. Examples also include the preparation of formulations and pharmacokinetic studies in rats at a dose of 50 mg/kg. Other examples revealed that the solubility of R-LA, at doses that refer to daily doses of LA used in clinical trials in an artificial gastric juice, was optimum only with the solution of this invention. Moreover, the in vitro activity of the claimed solution was evaluated using HepG2 and H2O2 challenged neuroblastoma SK-N-SH cell lines, showing a significant biological effect. Finally, a decrease in glucose was observed with R-LA in the solution of the invention using HepG2 cells, cultivated in a medium enriched with glucose. Hepatic lipid content may play a causal role in the development of insulin resistance. A composition of three hepatoprotective ingredients namely, zinc, LA and 1-deoxynojirimycin, (a constituent of mulberry leaves)


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according to the invention [71] can interact synergistically to provide health benefits associated with the maintenance of liver function. In the described in vitro examples, palmitic acid was added to HepG2 cells to induce steatosis (the accumulation of fat in the liver). Treatment with a combination of zinc, LA and 1-deoxynojirimycin, in addition to palmitic acid, reduced the relative lipid accumulation in hepatocytes. Among the combinations containing LA and expecting synergistic antidiabetic effect, are those comprising a meglitinide derivative and LA [72]. Meglitinide derivatives known as glinides affect insulin secretion. The invention discloses the preparation of tablets containing Nateglinide and LA, Repaglinide and LA as well as Mitiglinide and LA. The broad therapeutic potential of LA includes antiinflammatory properties and there is a need for alternative treatments for the management of inflammation that do not center on the use of NSAIDs to inhibit the production of pro-inflammatory mediators. The synergistic effect of a combination of avocado/soybean unsaponifiables (ASU) and LA is disclosed in the invention [73]. Clinical studies have reported the beneficial effects of ASU in human and equine osteoarthritis patients. In vitro studies using bovine and human joint tissue cells have shown that ASU inhibits the expression and the production of cytokines, chemokines, prostaglandin E2 (PGE2), nitric oxide and metalloproteinases. This invention provides for methods comprising administration of ASU and LA or derivatives thereof to a mammalian subject. In vitro experiments using chondrocyte cultures activated with lipopolysaccharide (LPS) or H2O2 showed that the combination of ASU and LA at concentrations 2.5 and 1.25 µg/mL reduced PGE2 levels to more than either ASU or LA alone. No examples using LA derivatives are provided. LA can replace polysorbates such as TWEEN 80 as solubilizers of docetaxel. In consideration of the severe side effects associated with the use of polysorbates, the invention [74] discloses the preparation of single-vial sterile injection concentrates containing docetaxel and small amounts of LA, ready to be combined with an infusion solution for administration to patients. Results of the stability tests of single-vial sterile injection concentrates up to 12 months are included, confirming the stability of the formulation at 40 or 25 C. Finally, composition comprising LA or a derivative thereof can be used as antimicrobial agent. The invention [75] provides a method for preventing or reducing the growth or proliferation of microorganisms attached to the surface of a medical device or the surface of a subject’s body. Specifically, the preparation of an impregnating solution containing LA dissolved in formic acid, ortho-phosphoric acid, glycerol and KCl is described. Catheter segments treated with LA, lipoamide or DHLA had fewer or bacterial cells adhered to them. Additionally, LA and its derivatives in combination with an antibiotic (gentamicin, doxycycline or levofloxacin) displayed significant synergistic antimicrobial activity. 996

LA conjugates The development of multifunctional therapeutic tools is a promising approach against complex diseases. LA represents a lead chemical moiety for the design and synthesis of multitarget-directed drugs with minimal unwanted side effects. In this context, patent applications and publications [26,34-38,49,50] of various groups for the last 4 years, deal with the synthesis of conjugates combining LA with other pharmacophores in one scaffold. 2.2

Anti-inflammatory LA conjugates Two recent applications describe methods for treating or preventing diseases that have inflammation as underlying component. The invention, [76], aiming to reduce the side effects of salicylates, is based on the discovery of LA-salicylate derivatives and their demonstrated effects in achieving improved treatment that cannot be achieved by administering LA or salicylate alone or in combination. Conjugates are able to be hydrolyzed and to produce free LA and salicylate. The application provides general experimental methods for the synthesis of a variety of conjugates and 10 Schemes. No spectroscopic or other analytical data are included, except for compounds 1a -- d and 2 depicted in Figure 2. Although the biological assays using Raw Macrophages are described in detail, specific data using the claimed compounds are not reported. The invention [77] provides bifunctional compounds combining in one scaffold a poly(ADP-ribose) polymerase (PARP) inhibitor and a ROS scavenger or cyclic nitroxide moieties for prevention, treatment or management of diseases, disorders and conditions associated with elevated PARP activity or expression. PARP activation is implicated in the regulation of inflammatory mediators and in exhaustion of adenosine triphosphate (ATP). Moreover, it is known that superoxide anion is an activator of PARP. Among compounds of a general structure A-X-B (A = PARP inhibitor, B = 1,2-dithiolanyl, or cyclic nitroxide moieties) preferred compounds are 26 depicted in tables. Synthetic schemes, procedures and spectroscopic and analytical data are included for compounds 3, 4 synthetic schemes for 5. Evaluation of the in vitro PARP inhibitory activity of compound 3 as well as of the cytoprotective activity using RAW cells exposed to H2O2 is reported. Moreover, the effect on lung myeloperoxidase (MPO) activity in rodent model of inflammation showed that compound 3 at a dose of 60 mg/kg reduces inflammation and histological injury, compared to placebo, while at a dose of 30 mg/kg reduced elevation of MPO in a murine model of chlorine inhalation lung injury. 2.2.1

Analgesic LA conjugates LA esters or amides are claimed to be effective for the treatment of pain. The disclosure [78] relates to a LA conjugates, the method for the preparation and detailed analytical data of all the intermediates and the final compound 6, as well as methods for testing (neuropathic pain in rats) this compound. 2.2.2



COOH

O

O

HO

X

N H OH

N H

S

O N H

S

NH2

O


O

N H

O

N

4

N

3

4

S 4

N

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N HN H

5

H N

O

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O

N

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6

NH2

S S

O

O

O

S O

N H

S

O

NH2

S S

N

S

2

1a X = -CH2CH21b X = -CH2CH2OCH2CH21c X = -CH2CH2SSCH2CH21d X = -CH2CH2NMeCH2CH2-

O

7

S

S S

S

O

O

O

S

O

O H O

8

O

O

H OH

N

S

H O

9

H OH

N

S

O

7

7

O

7

N

O

S

O

OH

N S S

14

O

S

13

O O O

S

O

O

7

O S

O

O

O

7

7

O

S

O

12

N N

O

7

7

N H

10 X = H 11 X = Na

O O

HS HS

COOX

O N H

PO3H2

N H

15

COOH O N H

S S

16

SO3H

O

H N

COOH

O

O N H

S S

COOH S S

17

O

N

18

O

O O

O

O

O S S

19

O

O

O

O S S

S

OH

O O

21

20 O O2N

N

OH

O O

O O

S

O

OH O

O

S O

CN

HO

O

O

S

O

SO3H

O

O N

N H

22

Figure 2. LA conjugates described in the reviewed patents.


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In vivo assays are described in detail, they included two different dose regiments as well as control and gabapentin (positive control)-treated groups of animals. The final compound at a dose of 150 mg/kg was effective in treating the spinal nerve ligation model of neuropathic pain in rats. This activity was similar to that of gabapentin. The same inventor discloses in the application [79] detailed experimental procedure for the synthesis of the claimed compound 7 and included the same in vivo tests described in his previous application. Compound 7 demonstrated prolonged analgesic activity compared to gabapentin, while its activity in spinal nerve ligation model of neuropathic pain was comparable to gabapentin. Although the dosages expressed in mg incommode comparisons of the activity due to the differences of the molecular weights (MW of gabapentin 171.2 and MW of the LA derivative 438.6), the claimed compound displays a superior therapeutic profile compared to gabapentin. A third application of the inventor [80] exemplifies a huge number of derivatives, with description of the synthesis of only two compounds 8 and 9 while biological data are not given. The invention [81] pertains to LA conjugates with L-carnosine and describes the synthesis of compound 10 and in vivo pharmacological test. Specifically, the effect of the sodium salt of the racemic compound 10 (compound 11) was evaluated in a rat model of mononeuropathy (paw pressure test) with a dose per os of 30 mg/kg demonstrating the greater effectiveness, on osteoarthritis induced pain with an analgesic effect up to 45 min at a dose of 10 mg/kg and up to 60 min at a dose of 30 mg/kg as well as on oxaliplatin-induced pain (effective at 30 mg/kg). Moreover, the effect of compound 11 on mice using the hot plate test was evaluated achieving a high analgesic effect. The dose of 30 mg/kg (MW 436.5) did not alter the behavioral parameters of mice while the reduction of the number of writhes was comparable to ibuprofen (MW 206.3) at a dose of 100 mg/kg.

LA conjugates for the treatment of obesity diabetes

2.2.3

LA and/or DHLA esterified with diacylglycerol (DAG) may be used as nutraceuticals and/or pharmaceuticals for the prevention and treatment of obesity, diabetes and other oxidative stress-related diseases [82]. Compounds disclosed in this application are usable as antioxidants, stabilizers, emulsifiers in food. Antioxidant activity was evaluated using DPPH. In vivo tests using seven groups of rats revealed that DAG--DHLA 12 at a dose of 200 mg/kg block food intake after 4 h. Rather similar result was observed with DAG-LA 13 conjugate, suggesting that these compounds could enhance body weight loss. Although the application claims all possible regioisomers on glycerol backbone and alkyl chains of 3 -- 21 carbon atoms, and up to six double bonds, only two compounds (1,3-dioleoyl-glycerol derivatives) were synthesized. 998

LA conjugates against ischemia/reperfusion damage

2.2.4

The invention [83] claims a variety of Danshensu (one of the major active ingredients of Chinese herbal medicine) derivatives, their synthesis, evaluation of their antioxidant activity, MTT assay on primary cardiac cells as well as their effect on infarct size. Examples include among others detailed synthetic procedure (starting from Danshensu, its conversion to ester with ethyl trimethyl-pyrazine), for the preparation of LA conjugate LDTM 14. However, biological data for this compound are not provided. The patent application [84] exemplifies the synthesis of 35 LA conjugates with amino acids and the in vivo evaluation of their effect on infarct size reduction in a rat model of myocardial infarction/reperfusion injury. A significant reduction in the area of cardiac damage was observed in myocardial tissue sections following treatment with doses up to 20 mg/ kg of the compounds. RLip-aminoethylphosponic acid 15 was the most active compound reducing infarct size by 50% at a dose of 3 mg/kg. Furthermore, the efficacy of selected lipoyl compounds of the invention in a PAC rat model of ischemia-induced renal injury. Compound 15, at 10 , 3 and 1 mg/kg, RLip-EA-OH (16) at 10 mg/kg; RLip-Cya-OH (17) at 3 mg/kg; RLip-Tau (18) at 3 mg/kg; were administered intravenously as a bolus dose 15 min prior to ischemia. The tested compounds effectively reduced serum creatinine, up to 76% (compound 15 at 10 mg/kg) relative to the control animals and minimized renal ischemic injury. Anticancer LA conjugates LA conjugates is a promising approach against other multifactorial pathological conditions like cancer. The invention [85] claims the preparation of nanospheres formed from LA conjugates with NSAID, camptothesin (anticancer) or statins containing hydrophobic compounds, for diagnosing or treating cancer and preventing cardiovascular disease. Examples include preparation of nanospheres and the synthesis of bifunctional derivatives of LA and NSAIDs (LA--TEG [teraethylene glycol] --LA, LA--TEG--Ind [indomethacin], LA--TEG--Ibu [ibuprofen], LA--TEG--Npx [naproxen]), which had been reported in previous patent applications and publication of these inventors. Camptothecin (CPT) prodrug 19 was synthesized by introducing biodegradable carbonate and ester bonds. Spontaneous emulsification of the prodrug and a-tocopherol abates problems associated with free delivery of the highly hydrophobic prodrug. The preparation of fluorescent labeled antioxidant--antineoplastic nanospheres is described. The invention includes examples on the in vitro cellular uptake and in vivo antitumor effect of CPT--TEG--LA nanoprodrug. Two recent Chinese applications deal with anticancer LA derivatives. The invention [86] discloses DHLA saccharide derivatives, their preparation and evaluation of the in vitro antitumor activity of a LA saccharide derivative using cancer cells such as A549, SW872-S and NCI-H460. The LA 2.2.5



hydrazides could prevent or cure tumor diseases, according to the invention [87] that describes their preparation and evaluation of antitumor activity on various cancer cell lines.

inflammatory processes and age-associated diseases, while LDOG-SS- could ensure a slow release of LA. 3.

Neuroprotective LA conjugates LA scaffold has inspired the design and synthesis of a large number of multi-target-directed agents against neurodegeneration 27 [38]. Thus, the application [88] discloses conjugates of LA and apocynin possessing antioxidant and neuroprotective properties. Apocynin is a major active ingredient of rhizomes, used as herbal medicine to treat inflammatory diseases. Compound 20 was synthesized and was tested in vitro using N27 neuronal cells exposed to t-butyl peroxide and in vivo in various stroke models using rats subjected to middle cerebral artery occlusion (MCAO), measuring the infarct size reduction. Furthermore, the effect of pre-administration of 20 in rats (30-min pre-MCAO) on endogenous antioxidants, DNA fragmentation was evaluated. The invention also includes stability studies of the compound in buffer as well as metabolic stability studies using rat and human liver microsomes. Compound 20 produced dose-dependant, short-term neuroprotection (5.5 h of reperfusion). Significant neuroprotection was observed at a dose of 0.1 mg/kg manyfold less compared to doses required for apocynin or LA on their own. A detailed discussion is included concerning the results of the in vivo experiments and the mode of action of compound 20. However, the tested compound was unstable in biological matrix. Other LA conjugates against cerebral ischemia/reperfusion damage are disclosed in the invention [89]. Specifically, ginkgolide B derivatives combining a platelet-activating factor receptor antagonist ginkgolide B as a parent nucleus and an antioxidant group, edaravone or LA are claimed. In vivo experiments using a model of ischemia/reperfusion in rats showed that compound 21 reduce infarct size and has low toxicity. Tolcapone (a selective, inhibitor of catechol-O-methyl transferase, COMT) conjugates could be used for the treatment of Parkinson’s disease according to the application [90], which claims numerous compounds among them 22, the synthesis of which is described. No analytical or biological data are disclosed.


2.2.6

LA conjugates for topical application Lipoate- or dihydrolipoate-substituted acylglycerols could be used as carriers for LA for topical and cosmetic applications. In this context, lipoyl dioleoylglycerol (LDOG-SS-) was enzymatically prepared by lipase-catalyzed trans-esterification and its antioxidant potential was evaluated in liposomal vesicles [91]. LDOG-SS- (disulfide form) and dihydrolipoyl dioleoylglycerol (LDOG-SH, dithiol form), were incorporated into large, unilamellar vesicles of dioleoylphosphatidylcholine. Topically applied, the claimed molecules may decrease oxidative stress in (epi)dermal tissues, and thereby prevent 2.2.7

Conclusion

Several publications and patents were devoted to LA and its conjugates in the last 4 years indicating that these molecules remain a promising approach for the prevention or treatment of various diseases. Among the reviewed inventions, summarized in Table 1, numerous claim combinations of LA with other bioactive compounds, to be used as NSs. Moreover, recent patent applications deal with the preparations of LA salts or solutions aiming to improve its stability and its pharmacokinetic parameters. Finally, LA conjugates possessing anti-inflammatory, analgesic, anti-cancer, antidiabetic or neuroprotective activity represent an interesting approach as multi-target-directed agents against complex diseases. 4.

Expert opinion

LA displays an impressive array of biological functions and attracted a tremendous interest from the research community and the general public. LA is used as a nutritive supplement and as therapeutic agent. From a typical diet only trace amounts of LA can be uptaken. Thus, all information for its activity and bioavailability comes from studies using exogenous-administrated LA. Most commercially available LA supplements are a mixture of R and S enantiomers. The precise mechanism and the effect of LA enantiomers in various pathological conditions are not fully clarified. Although in some studies R-LA and S-LA are equipotent, it has to be established whether R-LA, or a racemic mixture would be best to use for a specific disorder, in future clinical studies. Other problems associated with the administration of LA, is its rapid clearance and its tendency to polymerize. Since the stability of LA is a major issue, four [64,68-70] of the reviewed patents propose the preparation of salts or solutions to overcome this problem. Furthermore, appropriate salts or esters of LA could modulate the release of LA and control its uptake, thus ensuring a more intense and lasting activity. On the other hand, the presence of LA moiety affects the lipophilicity of the drugs and thus influences their uptake. It is known that cellular uptake of LA is mediated by the sodium-dependent multivitamin transporter, SMVT, a system that could be targeted for delivering drugs with poor permeability [92,93]. Although hundreds of LA derivatives have been synthesized and various uses have been the subject of publications and patent applications, only LA is currently in clinical use for the treatment of diabetic neuropathy and endothelial dysfunction. LA has been used in Germany for over 50 years as a therapy for diabetic neuropathy and retinopathy. Additionally, a number of clinical trials have been undertaken using


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Table 1. Recent patent applications on LA and its derivatives. WO2012178014 US20130034632 US20130045273 US20130183277 WO2013156971


EP2386552 WO2011152658

WO2013018008

WO2013007447 WO2013115740 WO2012162063

WO2013022969 WO2013181529 US20110082192 US2011141909

US20110237658 US20120022147 WO2013168011 WO2011080725 WO2011078785 WO2012103813 WO2012067947

WO2013016696 CN103360437 CN102757425 WO2013071400 CN103242337 WO2013168023 US8455666

Compositions containing methylphenidate as CNS medication with acetyl L-carnitine, L-tyrosine, NAC and LA for the treatment of chronic fatigue. Patients showed a mean fatigue symptom reduction of 41 -- 54% Bilayer tablets containing LA and NAC to increase stability of the ingredients and be used as nutritional supplement Nutritional supplements containing LA and NAC administered to healthy individuals to increase the levels of GSH and vitamin C, as well as glutathione S-transferase activity in the blood Nutrient composition, including LA, acetyl L-carnitine and NAC, which reduced copies in HIV RNA viral load and significantly increased CD4 counts in patients with peripheral neuropathy induced by antiviral therapy. Composition comprising LA and honokiol and its effects on a primary cell culture of rat cortical neurons. Best results were obtained with LA 95.5%--honokiol 4.5% and LA 91%--honokiol 9% Process for the preparation of R-LA salts, their formulation in form of tablets Pharmaceutical composition containing LA salt with piperazine and the antidiabetic drug glimepiride for the treatment of type 2 diabetes. In vitro evaluation revealed that the claimed medication was more effective than the individual components LA and glimepiride Preparation of a solution of LA in order to overcome stability and bioavailability problems of LA and evaluation of cytoprotective activity using HepG2 and H2O2 challenged neuroblastoma SK-N-SH cell lines. Pharmacokinetic studies in rats at a dose of 50 mg/kg Composition of three hepatoprotective ingredients namely, zinc, LA and 1-deoxynojirimycin, and in vitro evaluation of its effects Tablets containing LA and meglitinide derivatives, which affect insulin secretion Compositions comprising avocado/soybean unsaponifiables (ASU) and lipoic acid to treat osteoarthritis. Combination of ASU and LA at concentrations 2.5, 1.25 µg/ml reduced PGE2 levels more than either ASU or LA alone Docetaxel formulations with LA and stability tests of single-vial sterile injection concentrates Antimicrobial LA compositions against microorganisms attached to the surface of a medical device or of a subject’s body LA-salicylate derivatives, for treating inflammatory diseases. Biological evaluation is not reported Anti-inflammatory bifunctional compounds combining in one scaffold a poly(ADP-ribose) polymerase inhibitor and LA. In vitro and in vivo evaluation of one LA conjugate that reduces inflammation and myeloperoxidase (MPO) activity at doses of 30 and 60 mg/kg LA conjugates. Synthesis of one compound and evaluation using an in vivo model of neuropathic pain 2,6-xylidine-LA conjugate for the treatment of pain. The claimed compound displayed superior activity compared to gabapentin LA conjugates with opoids for the treatment of chronic pain. Biological evaluation is not reported LA conjugates with carnosine. Synthesis of one compound and its sodium salt. The latter was evaluated in vivo and displayed significant analgesic and anti-hyperalgesic efficacy at a dose of 30 mg/kg Diacylglycerol-based LA derivatives. Synthesis of two conjugates, which at a dose of 200 mg/kg blocked food intake in rats Danshensu derivative of LA, as cardioprotective agent. Biological evaluation is not reported Synthesis of 35 LA conjugates with amino acids and in vivo evaluation of their effect against myocardial and renal ischemia/reperfusion damage. Administration of some analogs at doses of 1 -- 10 mg/kg significantly reduced infarct size Nanospheres formed from LA conjugates with NSAID, camptothesin or statins, in vitro cellular uptake and in vivo antitumor effect of CPT-TEG-LA nanoprodrug Dihydrolipoic acid saccharide derivatives, preparation and evaluation of the in vitro antitumor activity Preparation of LA hydrazides and evaluation of antitumor activity Conjugates of LA and apocynin possessing antioxidant and neuroprotective properties. In vivo experiments (stroke models) with one compound, showed significant neuroprotection at a dose of 0.1 mg/kg Ginkgolide B conjugates with LA or DHLA inhibit platelet aggregation, scavenge free radicals and reduce the cerebral infarct size in rats Catechol-O-methyl transferase inhibitor/LA hybrids for the treatment of PD. Biological evaluation is not reported LA and DHLA substituted acylglycerols incorporated into large, unilamellar vesicles, to be used as carriers for LA for topical applications. Enzymatic synthesis, evaluation of the lipid peroxidation inhibition, in a model membrane system

LA supplements up to 2400 mg/day with no evidence of serious side effects [94-100]. Combinations of LA with well-known drugs as well as the synthesis of LA conjugates with other bioactive scaffolds are two strategies toward the development of effective agents 1000

for the prevention or treatment of various disorders and diseases. According to the reviewed patents, LA can be used in combination therapy, with drugs (anticancer, antidiabetic, antimicrobial) displaying synergistic effects and reduced toxicity.




Numerous publications and patents of this review claim synthetic LA conjugates with other bioactive moieties, aiming to target multiple pathways. The majority of these conjugates displayed higher activities than the parent compounds, resulting in lower doses. Moreover, this strategy may lead to reduced toxicity and could escape drug resistance. However, reliable preclinical and clinical trials are necessary to prove these possibilities. The lack of clinical trials using LA conjugate might be due to the lengthy process and cost of the development of a new drug. Regarding commercial available conjugates, only racemic lipocrine (a LA/tacrine conjugate) is currently marketed as a pharmacological tool for studying Alzheimer’s disease [101]. Four inventions [78-81] of this review describe LA conjugates for the treatment of pain, constituting the first reports on LA conjugates possessing analgesic activity. The inventors [81] recently published a more detailed investigation [102], on the mechanism of action of the claimed LA/carnosine--Na salt hybrid for neuropathic pain control. On the other hand, LA/carnosine--methyl ester hybrid attached to AuNPs displayed significant activity as carbonic anhydrase activator [57]. Although the reviewed patent applications do not disclose AuNPs functionalized with LA conjugates, this approach may have significant future biomedical applications. It should be noted that although some patents of the present review exemplify a large number of conjugates, they provide full experimental for one or few compounds. Biological and structure--activity data are very limited or they are completely missing. This information is necessary for the future development of these derivatives as drugs. Moreover, some LA conjugates are active at cellular level or in small animals, at high micromolar or even millimolar concentrations that cannot be clinically or physiologically relevant. Another issue concerning the synthesis of multifunctional derivatives of LA is that the synthesized derivatives reported so far are amides or esters of LA. Our team has reported [32,33] that the bioisosteric replacement of the amide group by

five-membered heteroaromatics such as 1,2,4- and 1,3,4oxadiazole, 1,2,3-triazole, isoxazole and tetrazole, influences the neuroprotective activity of the catechol--LA or chroman--LA conjugates, depending on the nature of heterocycle, probably because these heterocycles are potential pharmacophores. In addition, the presence of heteroaromatics could modify the stability and the pharmacokinetic profile of the resulting conjugates. Nevertheless, adequate in vivo tests are necessary to assess these possibilities. Formulations containing LA in a form ensuring its stability, or LA conjugates can have important applications as nutraceuticals or cosmeceuticals. LA conjugates, with other antioxidants or moisturizers, are potential anti-wrinkle and anti-ageing or skin-lightening agents, affording a controlled release by the action of skin enzymes, upon a topical application, as well as an increased stability of the formulations. Although the development of cosmeceuticals is a quite fast process, the use of nutraceuticals for the prevention of diseases/disorders or to delay ageing process requires clinical trials to study the long-term efficacy and health benefits of the formulations. LA and its conjugates endowed with various activities have an enormous potential to promote human health. However, clinical trials should be conducted to prove these beneficial effects.

Declaration of interest The author has 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. The author state no conflict of interest and has received no payment in preparation of this manuscript.


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Affiliation


Maria Koufaki Research Director, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48, Vas. Constantinou Ave. 11635 Athens, Greece Tel: +30 210 7273818; Fax: +30 210 7273831; E-mail: [email protected]


1005

Farnesoid X receptor modulators (2011 - 2014): a patent review.

Small molecule glucagon receptor antagonists: a patent review (2011 - 2014).

Ghrelin receptor modulators: a patent review (2011 - 2014).

Novel NF-κB inhibitors: a patent review (2011 - 2014).

PPARγ ligands and their therapeutic applications: a patent review (2008 - 2014).

Potential pharmacological uses of chalcones: a patent review (from June 2011 - 2014).

Transient receptor potential vanilloid type 1 antagonists: a patent review (2011 - 2014).

Podophyllotoxin derivatives: a patent review (2012 - 2014).

Neutrophil elastase inhibitors: a patent review and potential applications for inflammatory lung diseases (2010 - 2014).

Therapeutic contact lenses: a patent review.

Matrix metalloproteinase inhibitors: a patent review (2011 - 2013).

c-MET kinase inhibitors: a patent review (2011 - 2013).

Quinazoline derivatives as anticancer drugs: a patent review (2011 - present).

Systemic sclerosis: a systematic review on therapeutic management from 2011 to 2014.

A patent review of glucokinase activators and disruptors of the glucokinase--glucokinase regulatory protein interaction: 2011-2014.

5-Fluorouracil derivatives: a patent review (2012 - 2014).

Sodium channel blockers: a patent review (2010 - 2014).

DPP-4 inhibitors: a patent review (2012 - 2014).

Drugs for dengue: a patent review (2010-2014).

Caffeic acid derivatives, analogs and applications: a patent review (2009-2013).

Dammarane triterpenoids for pharmaceutical use: a patent review (2005 - 2014).

New substituted benzimidazole derivatives: a patent review (2013 - 2014).

Tranilast: a review of its therapeutic applications.

Coumarin derivatives: an updated patent review (2012-2014).