Synthesis and SAR of p38alpha MAP kinase inhibitors based on heterobicyclic scaffolds.
The synthesis and structure-activity relationships (SAR) of p38alpha MAP kinase inhibitors based on heterobicyclic scaffolds are described. This effort led to the identification of compound (21) as a potent inhibitor of p38alpha MAP kinase with good cellular potency toward the inhibition of TNF-alpha production. X-ray co-crystallography of an oxalamide analog (24) bound to unphosphorylated p38alpha is also disclosed.
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. murali.dhar@bms.com
T G
TG
Murali Dhar
Stephen T
ST
Wrobleski
Shuqun
S
Lin
Joseph A
JA
Furch
David S
DS
Nirschl
Yi
Y
Fan
Gordon
G
Todderud
Sidney
S
Pitt
Arthur M
AM
Doweyko
John S
JS
Sack
Arvind
A
Mathur
Murray
M
McKinnon
Joel C
JC
Barrish
John H
JH
Dodd
Gary L
GL
Schieven
Katerina
K
Leftheris
D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D001643:Bridged Bicyclo Compounds; D006571:Heterocyclic Compounds; D047428:Protein Kinase Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases