Discovery of 2-phenyl-3-sulfonylphenyl-indole derivatives as a new class of selective COX-2 inhibitors

2-Sulfonylphenyl-3-phenyl-indole derivatives have been reported to be highly potent and selective COX-2 inhibitors previously. In this paper, the regio-isomeric analogues-2-phenyl-3-sulfonylphenyl-indoles were identified as potent and selective COX-2 inhibitors. This work led to the discovery of compounds 4a and 8a possessing higher activity than Celecoxib on cellular assay.     

Synthesis and biological evaluation of substituted 2-sulfonyl-phenyl-3-phenyl-indoles: a new series of selective COX-2 inhibitors

A new series of substituted 2-sulfonyphenyl-3-phenyl-indole derivatives were synthesized and evaluated for their ability to inhibit COX-2 and COX-1enzymes. Most of the compounds synthesized were found to be highly potent and selective inhibitors of COX-2. This work led to the discovery of 2-aminosulfonylphenyl-3-phenyl-indole 5a which possesses higher activity and selectivity for COX-2 than Celecoxib both in vitro and in vivo.     

Synthesis and biological evaluation of 3-heteroaryloxy-4-phenyl-2(5H)-furanones as selective COX-2 inhibitors

A series of 3-heteroaryloxy4-phenyl-2-5H)-furanones were prepared and evaluated for their potency and selectivity as COX-2 inhibitors. This led to the identification of L-778,736 as a potent, orally active and selective inhibitor of the COX-2 enzyme.     

Design, synthesis, and biological evaluation of N-acetyl-2-(or 3-)carboxymethylbenzenesulfonamides as cyclooxygenase isozyme inhibitors

A group of N-acetyl-2-(or 3-)carboxymethylbenzenesulfonamides, possessing either a F or a substituted-phenyl ring substituent (4-F, 2,4-F2, 4-SO2Me, 4-OCHMe2) attached to its C-4 or C-6 position, was prepared using a palladium-catalyzed Suzuki cross-coupling reaction for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. Although N-acetyl-3-carboxymethyl-6-fluorobenzenesulfonamide [14, COX-1 IC50 = 2.26 microM; COX-2 IC50 = 0.012 microM; COX-2 selectivity index (SI) = 188] and N-acetyl-3-carboxymethyl-6-(4-isopropoxyphenyl)benzenesulfonamide (20c, COX-1 IC50 >100 microM; COX-2 IC50 = 0.15 microM; COX-2 SI >667) exhibited potent in vitro COX-2 inhibitory activity and high COX-2 selectivity, both compounds were inactive anti-inflammatory agents in a carrageenan-induced rat paw edema assay. In contrast, the less potent and less selective COX-2 inhibitors N-acetyl-2-carboxymethyl-4-fluorobenzenesulfonamide (12, COX-1 IC50 = 4.25 microM; COX-2 IC50 = 0.978 microM; COX-2 SI = 4.3), N-acetyl-2-carboxymethyl-4-(2,4-difluorophenyl)benzenesulfonamide (17c, COX-1 IC50 = 1.02 microM; COX-2 IC50 = 1.00 microM; COX-2 SI = 1.02), and N-acetyl-3-carboxymethyl-6-(4-methanesulfonylphenyl)benzenesulfonamide (20e, COX-1 IC50 = 0.109 microM; COX-2 IC50 = 1.14 microM; COX-2 SI = 0.095) exhibited moderate anti-inflammatory activity where a 75 mg/kg oral dose reduced inflammation 26%, 14%, and 20%, respectively, at 3 h postdrug administration relative to the reference drug aspirin where a 50 mg/kg oral dose reduced inflammation by 25% at 3 h postdrug administration.     

Selective COX-2 inhibitors. Part 2: synthesis and biological evaluation of 4-benzylideneamino- and 4-phenyliminomethyl-benzenesulfonamides

Two series of 4-benzylideneamino- and 4-phenyliminomethyl-benzenesulfonamide derivatives were designed and synthesized for the evaluation as selective cyclooxygenase-2 (COX-2) inhibitors in a cellular assay using human whole blood (HWB). Extensive structure-activity relationships (SAR) were studied within these series. Several compounds were found to be novel and selective COX-2 inhibitors. Among them, the most potent and selective was 4-(3-carboxy-4-hydroxy-benzylideneamino)benzenesulfonamide (20, LA2135), (IC(50)'s for COX-1: 85.13 microM; COX-2: 0.74 microM; SI: 114.5), being more active COX-2 selective than celecoxib.     

Synthesis and selective cyclooxygenase-2 (COX-2) inhibitory activity of a series of novel bicyclic pyrazoles

Novel series of pyrazolo[5,1-b]1,3-oxazolidines, pyrazolo[5,1-b]1,3-oxazines and imidazolidino[1,2-d]pyrazoles were synthesized. These compounds were evaluated in vitro for their ability to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in human whole blood (HWB). Several of the compounds were found to be novel and selective COX-2 inhibitors, the most potent and selective being 1-(5-cyclohexyl (2H,3H-pyrazolo[5,1-b]-1,3-oxazolidin-6-yl)-4-(methylsulfonyl)benzene, 7a (IC(5o) for COX-1>100 microM; for COX-2=1.3 microM).     

Synthesis and biological evaluation of 1,3,4-triaryl-3-pyrrolin-2-ones, a new class of selective cyclooxygenase-2 inhibitors

The synthesis and structure activity relationships (SAR) of a series of novel selective COX-2 inhibitors are reported. The results show that some of the 1,3,4-triaryl-3-pyrrolin-2-ones 1 are more potent as COX-2 inhibitors than celecoxib, and that lactam Id has the same selectivity.     

Pyridazinones as selective cyclooxygenase-2 inhibitors

Pyridazinone was found to be an excellent core template for selective COX-2 inhibitors. Two potent, selective and orally active COX-2 inhibitors, which were highly efficacious in rat paw edema and rat pyresis models, have been obtained.     

Cyclooxygenase-2 inhibitors constrict the fetal lamb ductus arteriosus both in vitro and in vivo

Nonselective cyclooxygenase (COX) inhibitors are potent tocolytic agents; however, they also have adverse fetal effects such as constriction of the fetal ductus arteriosus. Recently, selective COX-2 inhibitors have been used in the management of preterm labor in the hope of avoiding fetal complications. However, both COX-1 and -2 are expressed by cells of the ductus arteriosus. We used fetal lambs (0.88 gestation) to assess the ability of selective COX-2 inhibitors celecoxib and NS398 to affect the ductus arteriosus. Both selective COX-2 inhibitors decreased PGE(2) and 6ketoPGF(1alpha) production in vitro; both inhibitors constricted the isolated ductus in vitro. The nonselective COX-1/COX-2 inhibitor indomethacin produced a further reduction in PG release and an additional increase in ductus tension in vitro. We used a prodrug of celecoxib to achieve 1.4 +/- 0.6 microg/ml, mean +/- standard deviation, of the active drug in vivo. This concentration of celecoxib produced both an increase in pressure gradient and resistance across the ductus; celecoxib also decreased fetal plasma concentrations of PGE(2) and 6ketoPGF(1alpha). Indomethacin (0.7 +/- 0.2 microg/ml) produced a significantly greater fall in ductus blood flow than celecoxib and tended to have a greater effect on ductus resistence in vivo. We conclude that caution should be used when recommending COX-2 inhibitors for use in pregnant women, because COX-2 appears to play a significant role in maintaining patency of the fetal ductus arteriosus.     

A prodrug approach to COX-2 inhibitors with methylsulfone

2,2-dimethyl-4-phenyl-5-[4-(methylsulfinyl)phenyl]-3(2H)furanone derivatives, 3 and 6, were shown to be effectively transformed in vivo into the corresponding methylsulfone derivatives 1 and 4, when orally administered to rats. Pharmacological implications for use of sulfoxide analogues 3 and 6 are discussed as prodrugs to potent selective COX-2 inhibitors 1 and 4.     

QSAR studies on structurally similar 2-(4-methanesulfonylphenyl)pyran-4-ones as selective COX-2 inhibitors: a Hansch approach

QSAR analysis based on classical Hansch approach was adopted on two recently reported novel series of 2-phenylpyran-4-ones as selective cyclooxygenase-2 (COX-2) inhibitors. The 6-methyl derivatives of title compounds bifurcate as 3-phenoxypyran-4-ones (subset A) and 3-phenylpyran-4-ones (subset B) among series 1. Series 2 consists of 5-chloro derivatives of title compounds. Various regression equations were derived to study the influence of phenoxy and phenyl ring substituents of series 1 compounds on COX-2, COX-1 and selective COX-2 over COX-1 inhibitory activity. The best triparametric equation derived for 36 compounds of series 1 explains the hydrophobic, electronic and steric requirements for improved COX-2 inhibitory activity. QSAR model derived to explore the selective COX-2 over COX-1 inhibition showed that selectivity could be influenced by size and lipophilicity of substituents. The size of the first atom of 2 substituents appears to have negative effect on selectivity, whereas highly polar 3 substituents at R are favorable for improved selectivity. QSAR investigations on series 2 compounds revealed some interesting correlation of COX-2 inhibitory activity with calculated physicochemical properties of whole molecules. The positive logP confirms the hydrophobic interaction of series 2 compounds with COX-2 enzyme. The positive MR term indicates that an overall increase in size and polarizabilty of the molecules increases COX-2 inhibitory activity. The positive contribution of structural variable suggests biphenyl analogs are extremely potent COX-2 inhibitors.     

Selective COX-2 inhibitors. Part 1: synthesis and biological evaluation of phenylazobenzenesulfonamides

A series of phenylazobenzenesulfonamide derivatives were designed and synthesized for the evaluation as selective cyclooxygenase-2 (COX-2) inhibitors in a cellular assay using human whole blood (HWB) and an enzymatic assay using purified ovine enzymes. Extensive structure-activity relationships (SAR) were studied within this series, and several of selective COX-2 inhibitors have been identified. Among them, compound 8, 4-(4-amino-2-methylsulfanyl-phenylazo)benzenesulfonamide, showed a potent inhibitory activity to the cyclooxygenase enzymes (IC(50)'s for COX-1: 23.28 microM; COX-2: 2.04 microM), being active but less COX-2 selective than celecoxib.     

2-heterosubstituted-3-(4-methylsulfonyl)phenyl-5-trifluoromethyl pyridines as selective and orally active cyclooxygenase-2 inhibitors.

A series of novel 2-alkoxy, 2-thioalkoxy and 2-amino-3-(4-methylsulfonyl)phenylpyridines has been synthesized and shown to be highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. Structure-activity relationship studies have demonstrated that central pyridine ring substituents play an important role in the COX-2 potency, selectivity vs the COX-1 enzyme, and oral activity.     

Novel, potent and selective anilinoquinazoline and anilinopyrimidine inhibitors of p38 MAP kinase

SAR studies led to the identification of 4-(3-benzoylamino-6-methyl-anilino)quinazolines as potent and selective inhibitors of p38 MAP kinase. Further optimisation led to the identification of a series of 4-(3-benzoylamino-6-methyl-anilino)pyrimidines as potent inhibitors of the p38 MAP kinase signalling pathway in vitro and in vivo.     

Indolyl esters and amides related to indomethacin are selective COX-2 inhibitors

Previous studies from our laboratory have revealed that esterification/amidation of the carboxylic acid moiety in the nonsteroidal anti-inflammatory drug, indomethacin, generates potent and selective COX-2 inhibitors. In the present study, a series of reverse ester/amide derivatives were synthesized and evaluated as selective COX-2 inhibitors. Most of the reverse esters/amides displayed time-dependent COX-2 inhibition with IC₅₀ values in the low nanomolar range. Replacement of the 4-chlorobenzoyl group on the indole nitrogen with a 4-bromobenzyl moiety resulted in compounds that retained selective COX-2 inhibitory potency. In addition to inhibiting COX-2 activity in vitro, the reverse esters/amides also inhibited COX-2 activity in the mouse macrophage-like cell line, RAW264.7. Overall, this strategy broadens the scope of our previous methodology of neutralizing the carboxylic acid group in NSAIDs as a means of generating COX-2-selective inhibitors and is potentially applicable to other NSAIDs.     

Design and synthesis of 1,3-diarylurea derivatives as selective cyclooxygenase (COX-2) inhibitors

A group of 1,3-diarylurea derivatives, possessing a methylsulfonyl pharmacophore at the para-position of the N-1 phenyl ring, in conjunction with a N-3 substituted-phenyl ring (4-F, 4-Cl, 4-Me, 4-OMe), were designed and synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1/COX-2 isozyme inhibition structure-activity studies identified 1-(4-methylsulfonylphenyl)-3-(4-methoxyphenyl) urea (4e) as a potent COX-2 inhibitor (IC(50)=0.11 microM) with a high COX-2 selectivity index (SI=203.6) comparable to the reference drug celecoxib (COX-2 IC(50)=0.06 microM; COX-2 SI=405). The structure-activity data acquired indicate that the urea moiety constitutes a suitable scaffold to design new acyclic 1,3-diarylurea derivatives with selective COX-2 inhibitory activity.     

Design, synthesis and biological evaluation of benzo[1.3.2]dithiazolium ylide 1,1-dioxide derivatives as potential dual cyclooxygenase-2/5-lipoxygenase inhibitors

3-(4-Bromophenyl)-6-nitrobenzo[1.3.2]dithiazolium ylide 1,1-dioxide (5) was discovered as a new prototype for dual inhibitors of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX). Thus, the structure-activity relationships of benzo[1.3.2]dithiazolium ylide 1,1-dioxide skeleton were carried out. The 6-NO(2) group played an essential role in the inhibitory activity. In addition, moderate-sized lipophilic substituents at the para-position of the 3-aryl moiety were required for dual COX-2/5-LOX inhibitory activity. Among the identified potent dual inhibitors, 3-(4-tbutylphenyl) derivative 30c (IC(50) values of 0.27 μM and 0.30 μM against COX-2 and 5-LOX, respectively) and 3-(4-biphenyl) derivative 30f (IC(50) values of 0.50 μM and 0.15μM against COX-2 and 5-LOX, respectively) were the most potent dual COX-2/5-LOX inhibitors. Intraperitoneal administration of 30c at 100mg/kg demonstrated potent acute anti-inflammatory activity. As a result, benzo[1.3.2]dithiazolium ylide 1,1-dioxide represented a novel scaffold for the exploitation in developing dual COX-2/5-LOX inhibitors.     

4-Aryl/cycloalkyl-5-phenyloxazole derivatives as selective COX-2 inhibitors.

A series of 4-aryl/cycloalkyl-5-phenyloxazole derivatives was synthesized and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1). These compounds were found to be potent and selective COX-2 inhibitors.     

Design,synthesis, and biological evaluation of ketoprofen analogs as potent cyclooxygenase-2 inhibitors

A new series of ketoprofen analogs were synthesized to evaluate their biological activities as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 inhibition studies showed that all compounds were potent and selective inhibitors of the COX-2 isozyme with IC₅₀ values in the highly potent 0.057–0.085 μM range, and COX-2 selectivity indexes in the 115 to >1298.7 range. Compounds possessing azido pharmacophore group (8a and 8b) exhibited highly COX-2 inhibitory selectivity and potency even more than reference drug celecoxib. Molecular modeling studies indicated that the azido substituent can be inserted deeply into the secondary pocket of COX-2 active site for interactions with Arg⁵¹³.     

Synthesis and evaluation of dithiolethiones as novel cyclooxygenase inhibitors

3H-1,2-Dithiole-3-thiones substituted with a 3,5-di-tert-butyl-4-hydroxyphenyl (DTBHP) or a 3,5-di-tert-butyl-4-methoxyphenyl group at the C5 position were prepared and their ability to inhibit the cyclooxygenase isoenzymes, COX-1 and COX-2 was evaluated. Both compounds were potent inhibitors of COX-2 (relative to rofecoxib), and while the phenol was a weak inhibitor of COX-1, the methyl ether gave no measurable inhibition. Docking studies of the two compounds into the COX-1 and -2 active sites showed that the methyl ether could only fit in the COX-2 active site whereas the phenol could be docked into both COX-1 and -2. This study reports a new mode for inhibitor binding to COX-1 and -2 and a novel structural scaffold for the development of COX-2 selective inhibitors.