RESUMO
Series of aminopyridinecarboxamide-based inhibitors were synthesized and tested against human recombinant IKK-2 and in IL-1beta stimulated synovial fibroblasts. The 2-amino-5-chloropyridine-4-carboxamides were identified as the most potent inhibitors with improved cellular activity.
Assuntos
Aminopirina/química , Aminopirina/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Interleucina-1beta/antagonistas & inibidores , Amidas/química , Amidas/farmacologia , Sequência de Aminoácidos , Artrite Reumatoide/tratamento farmacológico , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Humanos , Quinase I-kappa B/metabolismo , Proteínas I-kappa B/química , Interleucina-1beta/metabolismo , Cápsula Articular/citologia , Dados de Sequência Molecular , Relação Estrutura-AtividadeRESUMO
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.