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J Med Chem ; 50(23): 5712-9, 2007 Nov 15.
Article in English | MEDLINE | ID: mdl-17948975

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.


Subject(s)
Antirheumatic Agents/chemical synthesis , Piperazines/chemical synthesis , Pyrazoles/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Antirheumatic Agents/chemistry , Antirheumatic Agents/pharmacology , Arthritis, Experimental/chemically induced , Arthritis, Experimental/drug therapy , Collagen , Crystallography, X-Ray , Male , Mice , Mice, Inbred DBA , Models, Molecular , Piperazines/chemistry , Piperazines/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Rats , Rats, Inbred Lew , Structure-Activity Relationship , p38 Mitogen-Activated Protein Kinases/chemistry
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