RESUMO
The preparation of the selective VEGF-R2 kinase inhibitor 10 (JNJ-17029259) is described in which the key precursor, 4-(5-isoxazolyl)benzonitrile, undergoes clean transformation to the corresponding cumylamine derivative with CeCl(3)-MeLi in THF. This high-yielding cerium mediated transformation is robust, reproducible, and readily scalable based on a requirement for the anhydrous CeCl(3) to be milled and subjected to ultrasound treatment prior to addition of methyllithium.
Assuntos
Cério/química , Césio/química , Cloretos/química , Compostos de Lítio/química , Nitrilas/química , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Ultrassom , Benzeno/química , Estrutura Molecular , Nitrilas/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
A novel series of 4-aryl-5-cyano-2-aminopyrimidines were synthesized and found to have potent VEGF-R2 kinase inhibitory activity. Structure-activity relationships were investigated and compound 14a was shown to be efficacious in a mouse model of corneal neovascularization.
Assuntos
Neovascularização da Córnea/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Pirimidinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Neovascularização da Córnea/patologia , Modelos Animais de Doenças , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Camundongos , Pirimidinas/síntese química , Relação Estrutura-AtividadeRESUMO
The series of 2-amino-4-aryl-5-chloropyrimidines was discovered to be potent for both VEGFR-2 and CDK1. Described here are the chemistry for analogue synthesis, SAR study, and its kinase selectivity prolifing. The full rat PK data and in vivo efficacy study are also included.
