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
Journal of Medicinal Chemistry2004Vol. 47(18), pp. 4517–4529
Citations Over TimeTop 13% of 2004 papers
Ping Chen, Arthur M. Doweyko, Derek Norris, Henry H. Gu, Steven H. Spergel, Jagabundhu Das, Robert V. Moquin, James C. 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 H. Thrall, Paul Stanley, Octavian Kocy, Mark R. Witmer, Steven B. Kanner, Gary L. Schieven, Joel C. Barrish
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.
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