Imidazoquinoxaline Src-family kinase p56Lck inhibitors:: SAR, QSAR, and the discovery of (S)-N-(2-chloro-6-methylphenyl)-2-(3-methyl-1-piperazinyl)imidazo[1,5-a]pyrido[3,2-e]pyrazin-6-amine (BMS-279700) as a potent and orally active inhibitor with excellent in vivo antiinflammatory activity

被引：54

作者：

Chen, P ^{[1
]}

Doweyko, AM ^{[1
]}

Norris, D ^{[1
]}

Gu, HH ^{[1
]}

Spergel, SH ^{[1
]}

Das, J ^{[1
]}

Moquin, RV ^{[1
]}

Lin, J ^{[1
]}

Wityak, J ^{[1
]}

Iwanowicz, EJ ^{[1
]}

McIntyre, KW ^{[1
]}

Shuster, DJ ^{[1
]}

Behnia, K ^{[1
]}

Chong, S ^{[1
]}

de Fex, H ^{[1
]}

Pang, SH ^{[1
]}

Pitt, S ^{[1
]}

Shen, DR ^{[1
]}

Thrall, S ^{[1
]}

Stanley, P ^{[1
]}

Kocy, OR ^{[1
]}

Witmer, MR ^{[1
]}

Kanner, SB ^{[1
]}

Schieven, GL ^{[1
]}

Barrish, JC ^{[1
]}

机构：

[1] Bristol Myers Squibb Pharmaceut Res Inst, Princeton, NJ 08543 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 18期

关键词：

D O I：

10.1021/jm030217e

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of novel anilino 5-azaimidazoquinoxaline analogues possessing potent in vitro activity against p56(Lck) and T cell proliferation have been discovered. Subsequent SAR studies led to the identification of compound 4 (BMS-279700) as an orally active lead candidate that blocks the production of proinflammatory cytokines (IL-2 and TNFalpha) in vivo. In addition, an expanded set of imidazoquinoxalines provided several descriptive QSAR models highlighting the influence of significant steric and electronic features. The H-bonding (Met319) contribution to observed binding affinities within a tightly congeneric series was found to be significant.

引用

页码：4517 / 4529

页数：13

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