The discovery of (R)-2-(sec-butylamino)-N-(2-methyl-5-(methylcarbamoyl)phenyl) thiazole-5-carboxamide (BMS-640994)-A potent and efficacious p38alpha MAP kinase inhibitor.
A novel structural class of p38alpha MAP kinase inhibitors has been identified via iterative SAR studies of a focused deck screen hit. Optimization of the lead series generated 6e, BMS-640994, a potent and selective p38alpha inhibitor that is orally efficacious in rodent models of acute and chronic inflammation.
Hynes
John
J
Bristol-Myers Squibb, Princeton, NJ 08543-4000, USA. john.hynes@bms.com
Wu
Hong
H
Pitt
Sidney
S
Shen
Ding Ren
DR
Zhang
Rosemary
R
Schieven
Gary L
GL
Gillooly
Kathleen M
KM
Shuster
David J
DJ
Taylor
Tracy L
TL
Yang
XiaoXia
X
McIntyre
Kim W
KW
McKinnon
Murray
M
Zhang
Hongjian
H
Marathe
Punit H
PH
Doweyko
Arthur M
AM
Kish
Kevin
K
Kiefer
Susan E
SE
Sack
John S
JS
Newitt
John A
JA
Barrish
Joel C
JC
Dodd
John
J
Leftheris
Katerina
K
D000818:Animals; D001168:Arthritis / Q000188:drug therapy; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C529303:BMS-640994; D065607:Cytochrome P-450 Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D003577:Cytochrome P-450 Enzyme System; D048308:Mitogen-Activated Protein Kinase 14