title: Synthesis, crystal structure, and activity of pyrazole-based inhibitors of p38 kinase.
abstract: 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.
authors.affiliation: Pfizer Global Research & Development, St. Louis Laboratories, 700 Chesterfield Village Parkway, Chesterfield, Missouri 63107, USA. matthew.j.graneto@pfizer.com
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Graneto
authors.forename: Ravi G
authors.initials: RG
authors.lastname: Kurumbail
authors.forename: Michael L
authors.initials: ML
authors.lastname: Vazquez
authors.forename: Huey-Sheng
authors.initials: HS
authors.lastname: Shieh
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Pawlitz
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Williams
authors.forename: William C
authors.initials: WC
authors.lastname: Stallings
authors.forename: Lifeng
authors.initials: L
authors.lastname: Geng
authors.forename: Ashok S
authors.initials: AS
authors.lastname: Naraian
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Koszyk
authors.forename: Michael A
authors.initials: MA
authors.lastname: Stealey
authors.forename: Xiangdong D
authors.initials: XD
authors.lastname: Xu
authors.forename: Richard M
authors.initials: RM
authors.lastname: Weier
authors.forename: Gunnar J
authors.initials: GJ
authors.lastname: Hanson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mourey
authors.forename: Robert P
authors.initials: RP
authors.lastname: Compton
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Mnich
authors.forename: Gary D
authors.initials: GD
authors.lastname: Anderson
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Monahan
authors.forename: Rajesh
authors.initials: R
authors.lastname: Devraj
mesh_terms: 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
chemical_list: 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