Journal of Scientific & Industri al Research

Vo l. 6 1. August 2002. pp 586-598

COX-2-Inhibitor - A New Class of Analgesic and Anti-inflammatory Drugs Mohd Ami r* and Shikha Kumar

Department of Pharmaceutical Chemi stry , Faculty o f Pharmacy, Jamia Hamdard, Hamdard Nagar. New Delhi ! 10 062

After more than a century o f use. pharmaco logists felt that they had discovered the mechani sm of acti on o f non­steroidal anti-inflammatory drugs (NSAIDs) when their inhibitory action on the producti on of prostaglandins was described . This ac tion was located at the inhibition o f the enzyme respo nsible for the conversion o f arachidonic acid to prostaglandins, namely cyclooxygenase. Recently, it has been recogni zed that more than one isoform o f the enzyme exists . The two forms o f cyclooxygenase described are widely diffe rent in their location, acti vity, and ro le. especially because the COX-I isoenzyme seems to be mainly a constituti ve enzyme, whereas the COX-2 isoenzyme is inducibl e. Thi s separation o f acti vity appears to be correlated with the separation o f functi on o f the various prostaglandins. whereas the constitutive form is associated with "phys iologic" functions and the induci ble form with infl ammatory responses. Recent advances have included the development of drugs with a hi gh specifi city towards the inducibl e enzyme (COX-2) to focu s on the anti-infl ammatory acti ons, because many o f the unwanted side e ffects o f NSAIDs have been associated with inhibiti on o f the constituti ve isoform (COX-I ). The present review di scusses the development of COX-2 inhibitors and their introduction in the market as useful drugs.

Introduction

Prostag landins (PGs) pl aya major role in the inflammation process, and the inhibition of PG production has been a common target of anti­inflammatory drug discove ry l.2. Nonsteroidal anti­inflammatory drugs (NSAIDs) that are active in reducing the pain and swe lling associated with inflammation, also affect other PG regulated processes, not associ ated with inflammation. Thus, ingestion of high doses of most common NSAIDs can produce side effects, including life-threatening ulcers that may limit the ir therapeutic potenti al3. NSAIDs ha ve been found to prevent the production of prostaglandins by inhibiting conversion of arachidonic ac id to PGs by the constituti ve cyc looxygcnase enzyme (COX- I) I.2 . In the 90s , a previously unknown enzyme in the human arachidoni c ac id/prostagland in pathway was di sco­ve red.l·G, and des ignated "cyc looxygenase II (COX-2) or pros tagland in GIH synthase II" .

COX- I is the constitu tive isoform and is ma inl y responsible for the synthes is of cytoprotecti ve prostaglandin s in the gastro in tes tina l trac t (GI) and of proaggregatory thromboxane in bl ood pl atele ts

3.

COX -2 is inducible and short li ved; its express ion is stimul ated in response to endotox in cytokines and

* Author for correspondence E-mail: ami rs @vsnl. net

. 7 8 I mltogens ' . COX-2 pays a maj or role In

prostaglandin biosynthesis in inflammatory ce lls (monocytes/macrophages) and in central nervous syste m9

.12

. These observations suggest that COX-l and COX-2 serve different physio logical and pathologica l functions. Class ical nonsteroidal anti­inflammatory drugs, (NSAIDs) inhibit , both COX-l and COX-2 to varying extent 13

.

The d ifferential tissue distribution of COX-l and COX-2 provides a rationale for the developme nt o f se lective COX-2 inhibitors as anti -infl ammatory and analges ic agent that lack the GI and hemato log ic liabiliti es exhibited by curre ntly marketed NSAIDs. T his hypothesis has been va lidated in animal mode ls and has led to the marketing of two di aryl heterocyc les celecox ib ( 1) and rofecoxib (2) as COX-2 inhi bitors 14.20 .

Literature Review

A literature survey revealed many se lect ive COX-2 inh ibitors. T wo distinct classes of aryl containing compound s have been independent ly reported by Gans ef al.21 OuP 697 (3) and Futak i et al. 22 NS-398 (4) that demonstrate an ti-infl ammatory activity in the rat es tabli shed adjuvant induced arthi riti s and without concomitant gastri c les ions. III vitro and with human recombinant COX-l and COX-2 enzyme have since confirmed that both OuP-697 (3) and NS-398 (4) are selective COX-2

)

AMIR & KUMAR: COX-2 INHIBITORS 587

. h' b' 23 24 S 'b 25 In I Itors '. el ert et al. reported that pyrazole SC-58125 (5) (COX-l IC50 > 100)lm, COX-2 IC50

=0.09)lm) is a selective inhibitor of the inducible form of human recombinant cyclooxygenase and is orally active in rat adjuvant induced arthiritis.

Prasit et al. 26 have reported that L-745,337 (6) is a selective COX-2 inhibitor with a potent anti­inflammatory activity in the rat adjuvant induced arthiritis model.

Reitz et al. 27,28 have reported novel 1,2-diaryl cyc10pentene methyl sui phones as COX-2 inhibitors. Compound SC-57666 (7) and SC-58231 (8) were found to be very potent COX-2 inhibitors and devoid of COX-1 activity.

Li et al. 29 have identified an extensive series of 1,2-diaryl cyclopentenes that act as potent and selective COX-2 inhibitors. Replacement of methyl sui phone moiety with a sulphonamide group on the second phenyl group was found to provide a substantial enhancement of in vivo potency, especially in the rat adjuvant-induced arthiritis model, albeit with some decrease in COX-2 selectivity. It is also reported that in vitro COX-l/COX-2 selectivity in sulphonamide series can be increased in many cases by simply incorporating a halogen atom at the 3-position of one of the phenyl ring. The selective COX-2 inhibitor sulphonamide (9) has been shown to be a remarkably orally active anti-inflammatory agent with no indication of GI toxicity.

Huang et al. 30 have reported a novel series of 5,6-diaryl spiro (2,4) hept-5-enes as highly potent and selective COX-2 inhibitors . Methyl sulphone (10) and sulphonamide (11) were shown to have superior in vivo pharmacological profiles, low GI toxicity and good oral bioavailability, and duration of action. They have also reported31 some diaryl indenes (12,13) and benzofurans (14,15) as potent and selective cyclooxygenase-2 inhibitors.

L · [37 h I et a. - ave reported novel terphenyl compounds that are selective COX-2 inhibitors and orally active anti-inflammatory agents. SAR studies have indicated that central ring substituent play an important role in COX-2 potency and only 1,2-diaryl 4,5-disubstituted benzene were found to be potent COX-2 inhibitors (16). Incorporation of two fluorine atoms in the central ring provide 1,2-diaryl 4,5-difluorobenzene sulphonamide which were very potent and highly selective COX-2 inhibitors.

A series of 1,2-diaryl pyrroles33 have been synthesized and found to contain potent and selective

inhibitors of the human cyclooxygenase-2 (COX-2) enzyme. Diarylpyrrole (17) is a potent and selective inhibitor, whereas the isomeric (18) is completely inactive against COX-2. But the isomeric sulphonamide derivative (19) is an excellent inhibitor ofCOX-2.

Khanna et al. 34 have reported a series of 1,2-diaryl imidazoles as highly potent and selective inhibitors of the human COX-2 enzyme. Different portions of diarylimidazole (20) were modified to establish SAR. Systematic vanatlons of the substituents in the aryl ring B have yielded very potent and selective inhibitors of the COX-2 enzyme.

A series of sulphonamide containing 1,5-diarylpyrazole35 derivatives were prepared and evaluated for their ability to block cyc100xygenase-2 (COX-2) in vitro and in vivo. Extensive structure activity relationship was carried out within this series and many potent and selective inhibitors of COX-2 were identified. Since an early structural lead SC-236 (21) exhibited an unacceptably long plasma half - life, several pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to identification of SC-58635, celecoxib (1) which is currently in use as a drug.

Aspirin is the only NSAID that covalently modifies both COX-l a'nd COX-2 by acetylating an active site serine residue (Ser-530 in COX-l and Ser-516 in COX-2). Aspirin is significantly more potent against COX-I than COX_236

. Kalgutkar et al.37

elected to structurally modify aspirin to a selective COX-2 inactivator. They synthesized and identified 2-acetoxy phenyl methyl sulphide (22) as a lead compound that demonstrated moderate inhibitory potency and selectivity for COX-2. Systematic structural modification led to the development of 2-acetoxy phenyl heptyl sulphide (23) which was found to have optimum COX-2 inhibitory potency. Introduction of a tripple bond in the 2-position gave 2-acetoxy phenyl hept-2-yl sulphide (24) which was the most potent and selective COX-2 inhibitor of the series. The compound was 60 - times more reactive against COX-2 than aspirin and 100 - times more selective for its inhibition38

.

Song et al. 39 have reported thiazolone and oxazolone derivatives of 2,6-di-tert-butyl phenol as selective COX-2 inhibitors. Initial mass screening and subsequent structure-activity relationship studies have

588 J SCI IND RES VOL 61 AUGUST 2002

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AMIR & KUMAR: COX-2 INHIBITORS

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590 J SCIIND RES VOL 61 AUGUST 2002

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identified (25) as the most potent and selective COX-2 inhibitors within the thiazolone and oxazolone series. They further reported40 1,3,4- and 1,2,4-thiadiazole derivatives of 2,6-di-tert-butylphenol as selective COX-2 inhibitors. Substituted 2,6-di-tert­butylphenols with structure (26-30) were identified as potent and selective COX-2 inhibitors. In 1,3,4-thiadiazole series when R=SH (26) , the compound was active but not very selective, slightly favouring COX-2. When R was changed from SH to SMe (27) more than 30 - fold increase in activity against both enzymes was observed. When R was changed from SMe to SEt (28) the potency against COX-2 was unchanged but the activity against COX-I was reduced more than 200-fold. Compound 28 was the most potent and selecti ve COX-2 inhibitor of the series. In the 1,2,4-thiadiazole series, an acidic proton on the side chain seems to be important for potency and selectivity. It was noted that thiadiazole (29) and oxadiazole (30) showed similar enzyme potency.

Cyclopentenones containIng a 4-(methyl sulphonyl) phenyl group in the 3 - position and a phenyl ring in the 2- position are selective inhibitors of cyclooxygenase-2 (COX-2). Black et 0l.41 have reported that the selectivity for COX-2 over COX-I is dramatically improved by substi tuting the 2-phenyl group with halogens in the meta - position or by replacing phenyl ring with 3-pyridyl ring. Thus the 3,5-difluoro phenyl derivative (31) and 3-pyridyl derivative (32) are particularly interesting as potential anti-inflammatory agents with reduced side effects profile. Both exhibit good oral bioavailibity and are potent in standard models of pain, fever, and inflammation, yet have a much reduced effects on the G I integrity of rats compared to standard non­steroidal anti-inflammatory drugs.

Puig et al. 42 have prepared a series of 3,4-diaryloxazolones and evaluated for their ability to inhibit cyclooxygenase-2. Extensive structure activity relationship identified several potent and selective COX-2 inhibitors. The replacement of methyl suI phone group on the 4-phenyl ring by a sulphonamide moiety resulted in compounds with superior in vivo anti-inflammatory properties. In the sulphonamide series the introduction of the methyl group at 5-position of oxazolone ring gave rise to a very selective COX-2 compound (33) but with decreased ill vivo activity. A selected group of 3,4-diaryloxazolones exhibited excellent oral activity when tested in acute and chronic assays of

inflammation, fever, and pain. Furthermore, these compounds were devoid of gastrointestinal toxicity at high doses. The overall pharmacological activity of the 3,4-diaryloxazolones suggests that these novel compounds constitute a promising series of oral anti­inflammatory agents with the potential for an improved side effects profile. Compounds (34-36) on the basis of their in vivo acti vity profi les and lack of gastrointestinal toxicity have been selected for further preclinical and clinical profiling.

Although diaryl heterocycles and other compounds have been extensively studied as selective COX-2 inhibitors, there are a few reports on the utilisation of well established NSAID template in the d · fl' COX 2 . I 'b ' 37.38.43·45 Of II eSlgn 0 se ectlve - In 11 Itors . a NSAIDs, indomethacin (37), zomeprac (38), asp irin (24), and flurbiprofen (39) are the only examples of compounds that have been successfully elaborated into selective COX-2 inhibitors.

Replacement of 4-chlorobenzoyl group of indomethacin with a 4-bromobenzyl moiety (37) generates a COX-2 selective inhibitors43

. In contrast,exchanging the carboxylate moiety in aspirin with alkylsulphide functionalities , affords specific COX-2 inhibitors37

.38

.

Kalgutkar et al. 46 have recently reported a biochemically based strategy for the facile conversion of carboxylic acid containing NSAIDs. Derivatisation of these compounds to esters and amides produces molecule, capable of binding tightly to COX-2 but not COX-I. Thus, conversion of carboxylic acid of indomethacin47 into esters (40) and amide (41) derivatives generates compounds that are potent and highly selective COX-2 inhibitors. Primary and secondary analogues of indomethacin were more potent COX-2 inhibitors than the corresponding tert amides.

Among the most potent and selective COX-2 inhibitors that have been identified is the 4-(5-methyl-3-phenyl isoxazol-4-yl) benzene sulphonamide, valdecoxib48 (42). Valdecoxib, potentially and selectively, inhibited a recombinant human COX-2 isoform with an ICso value of 0.005 11M as compared to a value of 140 11M obtained for a recombinant human COX-I isoform.

Talley et al. 49 tried to develop an injectable COX-2 inhibitor commenced with the idea of identifying a water soluble prodrug of valdecoxib that would undergo biotransformation in vivo. To test whether an acylated sulphonamide would serve as a

592

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J SCI IND RES VOL 61 AUGUST 2002

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The parecoxib sodium was found to be rapidly converted to valdecox ib ill vilro studies using human liver mic rosomes and ill vi vo studies conducted in rodent , dogs, and monkeys.

The ava ilability of safe and efficacious COX-2 inhibitors fo r ac ute pain management, particularl y post-surgical pain , constitute an important unmet medical need . Parecox ib sodium, a water soluble prodrug of va ldecoxib, was identified as a high ly potent and selective inhibitor of PGs from COX-2. Va ldecoxib is under co llaborative deve lopment by Pharmacia and Pfizer in the US and is licensed to Yamanollch in Japan and parecoxib sodium is being developed by Pharmacia and is also licensed to Yamanouch50

.

fn a new approach to diaryl heterocyc les COX-2 se lective inhibitors, Almas et al. 51 have investigated the attach ment of an additional six membered ring to the usual five membered central ring. The pyrazolo [ I,S-a l pyrimidine nucleus (44) was selected for the SAR study in view of the easier access to substituen t va riation in the extra ring in compari son to other possib le frame work.

Thus the synthes is and pharmacolog ical ac ti vity of a series of bicyclic pyrazolo [J ,S-a] pyrimidines , as potent and selecti ve cyc looxygenase-2 inhibitors, are described. The new compounds were eva luated ill vilro Ifor their ability to inhibit COX-J and COX-2 ac ti vity in human whole blood (HWB)] and ill vi vo [carrageenan induced paw oedema and air pouch model ]. Modificati on of the pyrimidine substituents showed that 6,7-disubstituted provided the best ac ti vi ty led to the identification of 3-(4-f1uoro­phenyl )-6, 7 -d i methy 1-2-( 4-methy Isul phony I phenyl) pyrazolo[I,S-a]pyrimidine (45) as one of the most potent and selec ti ve COX-2 inhibitors in this series.

Habeeb el al. 52 have recently reported the synthes is and anti-inflammatory properties of a series of diary lisoxazoles. The lead compound (46) in this group exhibited excellent ill vilro inhibitory potency aga inst COX-2 with no inhibition of COX-I. Many compounds in this group also showed impressive ac ti vity in an ill vivo model of inflam ation. Incorporation of C-S CF3 substituent on the central isoxazole ring enhanced selectivity towards COX-2.

4,S-dipheny l-4-i soxazoline53 (47) possessing various substituent (H, F, MeS, MeS0 2) at the p­position of one of the phenyl rings were synthes ized and evaluated as analgesic and selective COX-2 inhibitory anti··inflammatory agents. In the series the compound 2,3-dimethyl-S-(4-methyl sulphonyl phenyl)-4-phenyl-4-isoxazoline exhibited excellent analgesic and anti -inflammatory activities and it was a potent and selec ti ve COX-2 inhibitor (48).

Conclusions

The two recently developed and clinically ava il able selective COX-2 inhibitors, celecoxib and rofecoxib, are about 100- 1000 times more se lective on the COX-2 than on the COX- l isofonn. In Europe, rofecoxib is presently indicated for the symptoms and signs of osteoarthriti s, whereas celecoxi b is indicated for both osteoarthriti s and rheumatoid arthritis. The major clinical interest of these drugs is related to the lower incidence of gastrointest inal bleeding which, with the conventional COX-lICOX-2 agents has been a source of hosp itali sa tion, di sablement and death, espec ially in the elderl y. Clinical trials have convi nc ingly demonstrated that ce lecox ib and rofecoxib 111 clinica l use induce very few gastrointestinal compl ications, compared to conventional and non-selective NSAIDs. However the well known contraindicati ons for NSAlDs, such as late pregnancy, aspirin-induced asthma, congestive heart fai lure. and renal dysfunction, wi ll so far apply also to the COX-2 inhibitors. Fu rther research effort cu lminated in the discovery of another selective COX-2 inhibitor valdecoxib, which is useful in the treatment of osteoarthiriti s, rheumatoid arthiriti s, and pain . Agents, such as celecoxib and valdecoxib which are highly COX-2 spec ific and have shown excellent efficacy in reli eving inflammation and associated pain, unfortunately exhibit only modest aqueous solubility. In order to overcome the solubility restriction of these drugs, prod rug approac h was employed. The result has been the discovery of parecoxib sodium, a prodrug of valdecoxib, which can be given parenterally. Compared to the traditional and non-selective NSAIDs, COX-2 inhibitors may provide an insight into additional therapeutic areas, such as gastrointestinal cancer and dementia, where the potential relevance to COX-2 mechanisms are currently being explored and clinical trials being performed. With the rapid clinical acceptance of celecox ib, rofecox ib, valdecoxib, and parecox ib sodium, knowledge about their clinical usefulness in

AMIR & KUMAR: COX-2 INHIBITORS 595

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various inflammatory disease states and pai n disorders is increasing. For the many patients suffering from such conditions, the selective COX-2 inhibitors are likely to become a significant addition to the therapeutic arsenal of analgesic and anti­inflammatory drugs.

Acknowledgement

Authors thank the University Grants Commission New Delhi , for awarding a fellowship to Shikha Kumar in the form of financial ass istance.

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AMIR & KUMAR: COX-2 INHIBITORS 597

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