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.
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.
Chen
Ping
P
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
Doweyko
Arthur M
AM
Norris
Derek
D
Gu
Henry H
HH
Spergel
Steven H
SH
Das
Jagabundhu
J
Moquin
Robert V
RV
Lin
James
J
Wityak
John
J
Iwanowicz
Edwin J
EJ
McIntyre
Kim W
KW
Shuster
David J
DJ
Behnia
Kamelia
K
Chong
Saeho
S
de Fex
Henry
H
Pang
Suhong
S
Pitt
Sydney
S
Shen
Ding Ren
DR
Thrall
Sara
S
Stanley
Paul
P
Kocy
Octavian R
OR
Witmer
Mark R
MR
Kanner
Steven B
SB
Schieven
Gary L
GL
Barrish
Joel C
JC
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D016207:Cytokines / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011810:Quinoxalines / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D000893:Anti-Inflammatory Agents; C490499:BMS279700; D016207:Cytokines; D004791:Enzyme Inhibitors; D011719:Pyrazines; D011810:Quinoxalines; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases