RESUMO
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.
Assuntos
Quinase 2 de Adesão Focal/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Animais , Técnicas de Química Combinatória , Cristalografia por Raios X , Modelos Animais de Doenças , Desenho de Fármacos , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Humanos , Conformação Molecular , Estrutura Molecular , Osteoporose/tratamento farmacológico , Pirimidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
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.