RESUMO
An SAR study that identified a series of thienopyridine-based potent IkappaB Kinase beta (IKKbeta) inhibitors is described. With focuses on the structural optimization at C4 and C6 of structure 1 (Fig. 1), the study reveals that small alkyl and certain aromatic groups are preferred at C4, whereas polar groups with proper orientation at C6 efficiently enhance compound potency. The most potent analogues inhibit IKKbeta with IC50s as low as 40 nM, suppress LPS-induced TNF-alpha production in vitro and in vivo, display good kinase selectivity profiles, and are active in a HeLa cell NF-kappaB reporter gene assay, demonstrating that they directly interfere with the NF-kappaB signaling pathway.
Assuntos
Quinase I-kappa B/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Piridinas/química , Animais , Descoberta de Drogas , Células HeLa , Humanos , Quinase I-kappa B/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , NF-kappa B/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Transdução de Sinais , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Integration of computational methods, X-ray crystallography, and structure-activity relationships will be disclosed, which lead to a new class of p38 inhibitors that bind to p38 MAP kinase in a Phe out conformation.