1,2-DIARYLCYCLOPENTENES AS SELECTIVE CYCLOOXYGENASE-2 INHIBITORS AND ORALLY-ACTIVE ANTIINFLAMMATORY AGENTS

被引:209
作者
LI, JJ
ANDERSON, GD
BURTON, EG
COGBURN, JN
COLLINS, JT
GARLAND, DJ
GREGORY, SA
HUANG, HC
ISAKSON, PC
KOBOLDT, CM
LOGUSCH, EW
NORTON, MB
PERKINS, WE
REINHARD, EJ
SEIBERT, K
VEENHUIZEN, AW
ZHANG, Y
REITZ, DB
机构
[1] MONSANTO CO,SEARLE RES & DEV,DEPT INFLAMMATORY DIS RES,ST LOUIS,MO 63198
[2] MONSANTO CO,SEARLE RES & DEV,DEPT PHARMACOKINET BIOANALYT & RADIOCHEM,ST LOUIS,MO 63198
关键词
D O I
10.1021/jm00022a023
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of 1,2-diarylcyclopentene methyl sulfones and sulfonamides have been shown to be remarkably potent and selective cyclooxygenase-2 (COX-2) inhibitors. The methyl sulfone analogs 7 showed excellent COX-2 activity, with IC(50)s ranging from 0.003 (7f,n) to 0.87 (7o) mu(M. In addition, most analogs of 7 showed no activity (IC50 > 100 mu M) against the COX-1 enzyme. Replacement of the methyl sulfone moiety with a sulfonamide group gave a slightly more potent (typically 2-5-fold) but less selective COX-2 inhibitor, mainly due to an increase (20- > 100-fold) in COX-1 activity. However, in vitro COX-1/COX-2 selectivity for the sulfonamides 8 could be increased in many cases by simply incorporating a substituent at the 3-position of the phenyl group. Furthermore, in vitro selectivity increased with the size and number of substituents, as demonstrated in the selectivity trend of 8k (8000) > 8j (1900) > 8i (500) > 8h (100). More importantly, the sulfonamide COX-2 inhibitors showed greatly enhanced oral activity in the rat model of established adjuvant-induced arthritis, with inhibition values of 79.0% (8a), 81.5% (8c), and 83.0% (8g) at 1 mg/kg. On the basis of its overall biological profile, sulfonamide 8c was evaluated as a potential clinical candidate, displaying an ED(50) of 22 mpk in the rat carrageenan-induced paw edema model and an ED(50) of 0.16 mpk in the rat established adjuvant-induced arthritis model with no indication of gastrointestinal toxicity in rats and mice at 200 mpk. In addition, a preparative-scale synthetic route to sulfonamide 8c has been developed.
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收藏
页码:4570 / 4578
页数:9
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