RESUMEN
The synthesis and SAR for a series of diaminopyrimidines as PYK2 inhibitors are described. Using a combination of library and traditional medicinal chemistry techniques, a FAK-selective chemical series was transformed into compounds possessing good PYK2 potency and 10- to 20-fold selectivity against FAK. Subsequent studies found that the majority of the compounds were positive in a reactive metabolite assay, an indicator for potential toxicological liabilities. Based on the proposed mechanism for bioactivation, as well as a combination of structure-based drug design and traditional medicinal chemistry techniques, a follow-up series of PYK2 inhibitors was identified that maintained PYK2 potency, FAK selectivity and HLM stability, yet were negative in the RM assay.
Asunto(s)
Quinasa 2 de Adhesión Focal/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirimidinas/farmacología , Animales , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Diseño de Fármacos , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Humanos , Conformación Molecular , Estructura Molecular , Osteoporosis/tratamiento farmacológico , Pirimidinas/química , Ratas , Relación Estructura-ActividadRESUMEN
Novel classes of thienopyrimidines and thienopyridines have been identified as potent inhibitors of VEGFR-2 kinase. The synthesis and SAR of these compounds is presented, along with successful efforts to diminish EGFR activity present in the lead series.