Synthesis, Crystal Structure, and Activity of Pyrazole-Based Inhibitors of p38 Kinase

• Published in: Journal of medicinal chemistry Vol. 50; no. 23; pp. 5712 - 5719
• Main Authors: Graneto, Matthew J, Kurumbail, Ravi G, Vazquez, Michael L, Shieh, Huey-Sheng, Pawlitz, Jennifer L, Williams, Jennifer M, Stallings, William C, Geng, Lifeng, Naraian, Ashok S, Koszyk, Francis J, Stealey, Michael A, Xu, Xiangdong D, Weier, Richard M, Hanson, Gunnar J, Mourey, Robert J, Compton, Robert P, Mnich, Stephen J, Anderson, Gary D, Monahan, Joseph B, Devraj, Rajesh
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 15-11-2007
• Subjects: Animals; Antirheumatic Agents - chemical synthesis; Antirheumatic Agents - chemistry; Antirheumatic Agents - pharmacology; Arthritis, Experimental - chemically induced; Arthritis, Experimental - drug therapy; Biological and medical sciences; Collagen; Crystallography, X-Ray; Male; Medical sciences; Mice; Mice, Inbred DBA; Miscellaneous; Models, Molecular; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - chemistry; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Rats; Rats, Inbred Lew; Structure-Activity Relationship; Enzyme; Transferases; Mitogen-activated protein kinase; Inhibitor enzyme complex; In vitro; Modeling; Pyridine derivatives; Structure activity relation; Chlorine Organic compounds; Molecular model; Pyrazole derivatives; Binding mode; Inhibitor; Piperazine derivatives; Chemical synthesis; Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0611915

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 p38α. A compound identified from this series was efficacious in an animal model of rheumatic disease.