Synthesis, crystal structure, and activity of pyrazole-based inhibitors of p38 kinase.
A series of pyrazole inhibitors of p38 mitogen-activated protein (MAP) kinase were designed using a binding model based on the crystal structure of 1 (SC-102) bound to p38 enzyme. New chemistry using dithietanes was developed to assemble nitrogen-linked substituents at the 5-position of pyrazoles. Calculated log D was used in tandem with structure-based design to guide medicinal chemistry strategy and improve the in vivo activity of a series of molecules. The crystal structure of an optimized inhibitor, 4 (SC-806), in complex with p38 enzyme was obtained to confirm the hypothesis that the addition of a basic nitrogen to the molecule induces an interaction with Asp112 of p38 alpha. A compound identified from this series was efficacious in an animal model of rheumatic disease.
Graneto
Matthew J
MJ
Pfizer Global Research & Development, St. Louis Laboratories, 700 Chesterfield Village Parkway, Chesterfield, Missouri 63107, USA. matthew.j.graneto@pfizer.com
Kurumbail
Ravi G
RG
Vazquez
Michael L
ML
Shieh
Huey-Sheng
HS
Pawlitz
Jennifer L
JL
Williams
Jennifer M
JM
Stallings
William C
WC
Geng
Lifeng
L
Naraian
Ashok S
AS
Koszyk
Francis J
FJ
Stealey
Michael A
MA
Xu
Xiangdong D
XD
Weier
Richard M
RM
Hanson
Gunnar J
GJ
Mourey
Robert J
RJ
Compton
Robert P
RP
Mnich
Stephen J
SJ
Anderson
Gary D
GD
Monahan
Joseph B
JB
Devraj
Rajesh
R
D000818:Animals; D018501:Antirheumatic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy; D003094:Collagen; D018360:Crystallography, X-Ray; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
C525468:1-(5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl)-4-methylpiperazine; D018501:Antirheumatic Agents; D010879:Piperazines; D011720:Pyrazoles; D003094:Collagen; D048051:p38 Mitogen-Activated Protein Kinases