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 PMID: 15317463

Target-related Cytokines

2026-09-23

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

J Med Chem. 2004 Aug 26;47(18):4517-29. doi: 10.1021/jm030217e.

Ping Chen ¹ , Arthur M Doweyko , Derek Norris , Henry H Gu , Steven H Spergel , Jagabundhu Das , Robert V Moquin , James Lin , John Wityak , Edwin J Iwanowicz , Kim W McIntyre , David J Shuster , Kamelia Behnia , Saeho Chong , Henry de Fex , Suhong Pang , Sydney Pitt , Ding Ren Shen , Sara Thrall , Paul Stanley , Octavian R Kocy , Mark R Witmer , Steven B Kanner , Gary L Schieven , Joel C Barrish

Affiliations

Abstract

A series of novel anilino 5-azaimidazoquinoxaline analogues possessing potent in vitro activity against p56Lck 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.