文摘
A series of pyrazole inhibitors of p38 mitogen-activated protein (MAP) kinase were designed using a bindingmodel based on the crystal structure of 1 (SC-102) bound to p38 enzyme. New chemistry using dithietaneswas developed to assemble nitrogen-linked substituents at the 5-position of pyrazoles. Calculated log Dwas used in tandem with structure-based design to guide medicinal chemistry strategy and improve the invivo activity of a series of molecules. The crystal structure of an optimized inhibitor, 4 (SC-806), in complexwith p38 enzyme was obtained to confirm the hypothesis that the addition of a basic nitrogen to the moleculeinduces an interaction with Asp112 of p38. A compound identified from this series was efficacious in ananimal model of rheumatic disease.