2. Academic Validation
  3. 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

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

Affiliation

  • 1 Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
PMID: 15317463 DOI: 10.1021/jm030217e
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.

Figures
Products