Design and syntheses of diarylisoxazoles: Novel inhibitors of cyclooxygenase‐2 (COX‐2) with analgesic‐antiinflammatory activity

Abstract

A group of 4,5-diphenylisoxazoles (11ap), 3,4-diphenyl-5-trifluoromethylisoxazoles (15, 21), and 4,5-diphenyl-3-methylsulfonamidoisoxazole (23) possessing a variety of substituents (H, F, MeS, MeSO, MeSO 2 ) at the para-position of one of the phenyl rings were synthesized for evaluation as analgesic, and selective COX-2 inhibitory antiinflammatory (AI), agents. Although the 4,5-diphenylisoxazole group of compounds (11ap) exhibited potent analgesic and AI activities, those compounds evaluated (11a, 11b, 11m) were more selective inhibitors of COX-1 than COX-2, with the exception of 4-(4-methylsulphonylphenyl)-5-phenylisoxazole (11n) that showed a modest COX-2 selectivity index (SI) of 2.1. In contrast, 3-(4-methylsulphonylphenyl)-4-phenyl-5-trifluoromethylisoxazole (15), which retained good analgesic and AI activities, was a highly potent and selective COX-2 inhibitor (COX-1 IC 50 > 500 µM; COX-2 IC 50 < 0.001 µM) with a COX-2 SI of > 500,000, relative to the reference drug celecoxib (COX-1 IC 50 = 22.9 µM; COX-2 IC 50 = 0.0567 µM) with a COX-2 SI of 404. The 3-phenyl-4-(4-methylsulphonylphenyl) regioisomer (21) was a less potent inhibitor (COX-1 IC 50 = 252 µM; COX-2 IC 50 = 0.2236 µM) with a COX-2 SI of 1122, relative to the regioisomer (15). The related compound 4,5-diphenyl-3-methylsulfonamidoisoxazole (23) exhibited similar (to 21) potency and COX-2 selectivity (COX-1 IC 50 > 200 µM; COX-2 IC 50 = 0.226 µM) with an SI of 752. A molecular modeling (docking) study for the most potent, and selective, COX-2 inhibitor (15) in the active site of the human COX-2 enzyme showed the C-5 CF 3 substituent is positioned 3.37 Å from the phenolic OH of Tyr 355 , and 6.91 Å from the Ser 530 OH. The S-atom of the MeSO 2 substituent is positioned deep (7.40 Å from the entrance) inside the COX-2 secondary pocket (Val 523 ). These studies indicate a C-5 CF 3 (15, 21), or C-3 NHSO 2 Me (23), central isoxazole ring substituent is crucial to selective inhibition of COX-2 for this class of compounds. Drug Dev. Res. 51:273-286, 2000.

Gq-Dependent Signaling Upregulates COX2 in Glomerular Podocytes

“…24 As shown in Figure 3B, treatment with GqQϾL(ϩ) significantly enhanced PGE 2 generation compared with cells treated with GqQϾL(Ϫ). In the presence of the COX2 inhibitor, PGE 2 generation was significantly reduced in both GqQϾL(ϩ)-and GqQϾL(Ϫ)-treated cells.…”

NADPH Oxidase NOX5-S Mediates Acid-induced Cyclooxygenase-2 Expression via Activation of NF-κBin Barrett’s Esophageal Adenocarcinoma Cells

“…4E). In addition, a very selective COX2 inhibitor CAY10404 (39,40) also significantly diminished the basal production of PGE 2 in the culture medium of Barrett's cells and almost abolished the increase of PGE 2 production induced by overexpression of NOX5-S (Fig. 11E).…”

“…After a 4-h incubation, cells were washed three times and collected for measurement. E, a very selective COX2 inhibitor CAY10404 (39,40) significantly diminished the basal production of PGE 2 in the culture medium of Barrett's cells and almost abolished the increase of PGE 2 production induced by overexpression of NOX5-S. F, in these same cells as in E, CAY10404 significantly reduced the thymidine incorporation at the basal condition and partially inhibited the increase of thymidine incorporation caused by the overexpression of NOX5-S. Barrett's cells were cultured in the presence of vehicle (ethanol 0.1%) or CAY10404 10 Ϫ6 M for 48 h. Then a part of the culture medium was collected for PGE 2 measurement, and [ 3 H]thymidine was added. After a 4-h incubation, cells were washed three times and collected for measurement.…”

Evolution of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Cyclooxygenase (COX) Inhibition and Beyond

“…In addition, Knaus and coworkers showed that regioisomeric 3,4-diarylisoxazoles with a para-SO 2 Me substituents exhibit excellent in vitro COX-2 inhibitory activity and in vivo anti-inflammatory activities (103). For example, the isoxazole regioisomer 21 is a potent and highly selective COX-2 inhibitor (COX-2 IC 50 < 0.005 µM, COX-1 IC 50 > 500 µM; SI > 100,000) that is marketed by Cayman Chemicals as a research biochemical.…”