A three-step kinetic mechanism for selective inhibition of cyclo-oxygenase-2 by diarylheterocyclic inhibitors

被引：79

作者：

Walker, MC ^{[1
]}

Kurumbail, RG ^{[1
]}

Kiefer, JR ^{[1
]}

Moreland, KT ^{[1
]}

Koboldt, CM ^{[1
]}

Isakson, PC ^{[1
]}

Seibert, K ^{[1
]}

Gierse, JK ^{[1
]}

机构：

[1] Pharmacia Corp, Searle Discovery Res, St Louis, MO 63198 USA

来源：

BIOCHEMICAL JOURNAL | 2001年 / 357卷

关键词：

celecoxib; meloxicam; PGH(2) synthase; prostaglandin; valdecoxib;

D O I：

10.1042/0264-6021:3570709

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Cyclo-oxygenase (COX) enzymes are the targets for non-steroidal anti-inflammatory drugs (NSAIDs). These drugs demonstrate a variety of inhibitory mechanisms, which include simple competitive, as well as slow binding and irreversible inhibition. In general, most NSAIDs inhibit COX-1 and -2 by similar mechanisms. A unique class of diarylheterocyclic inhibitors has been developed that is highly selective for COX-2 by virtue of distinct inhibitory mechanisms for each isoenzyme. Several of these inhibitors, with varying selectivity, have been utilized to probe the mechanisms of COX inhibition. Results from analysis of both steady-state and time-dependent inhibition were compared. A generalized mechanism for inhibition, consisting of three sequential reversible steps, can account for the various types of kinetic behaviour observed with these inhibitors.

引用

页码：709 / 718

页数：10

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