RESUMEN
This Letter details the synthesis and evaluation of imidazo[4,5-b]pyridines as inhibitors of B-Raf kinase. These compounds bind in a DFG-in, αC-helix out conformation of B-Raf, which is a binding mode associated with significant kinase selectivity. Structure-activity relationship studies involved optimization of the ATP-cleft binding region of these molecules, and led to compound 23, an inhibitor with excellent enzyme/cell potency, and kinase selectivity.
Asunto(s)
Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Purinas/química , Purinas/farmacología , Animales , Células CACO-2 , Diseño de Fármacos , Humanos , Ratones , Simulación del Acoplamiento Molecular , Proteínas Proto-Oncogénicas B-raf/química , Proteínas Proto-Oncogénicas B-raf/metabolismo , Purinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
The synthesis and biological evaluation of non-oxime pyrazole based B-Raf inhibitors is reported. Several oxime replacements have been prepared and have shown excellent enzyme activity. Further optimization of fused pyrazole 2a led to compound 38, a selective and potent B-Raf inhibitor.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Pirazoles/síntesis química , Pirazoles/farmacología , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Oximas/química , Pirazoles/químicaRESUMEN
The past several years has seen research increasingly focused around the inhibition of tryptase, a mast cell protease implicated in a myriad of pro-inflammatory responses. Although few compounds have reached the clinic, several monobasic and multibasic small molecules have emerged as promising candidates as a treatment for asthma and other allergic and inflammatory disorders. This summary reviews recent patent activity of tryptase inhibitors and briefly outlines recent tryptase inhibitor literature and clinical updates.