The development of new bicyclic pyrazole-based cytokine synthesis inhibitors.
4-Aryl-5-pyrimidyl-based cytokine synthesis inhibitors of TNF-alpha production, which contain a novel bicyclic pyrazole heterocyclic core, are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production in a THP-1 cell-based assay and against human p38 alpha MAP kinase in an isolated enzyme assay. The X-ray crystal structure of a bicyclic pyrazole inhibitor co-crystallized with mutated p38 (mp38) is presented.
Townes
Jennifer A
JA
Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Rd, Mason, OH 45040, USA. townes.ja@pg.com
Golebiowski
Adam
A
Clark
Michael P
MP
Laufersweiler
Matthew J
MJ
Brugel
Todd A
TA
Sabat
Mark
M
Bookland
Roger G
RG
Laughlin
Steve K
SK
VanRens
John C
JC
De
Biswanath
B
Hsieh
Lily C
LC
Xu
Susan C
SC
Janusz
Michael J
MJ
Walter
Richard L
RL
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D011720:Pyrazoles; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases