RESUMO
Abrogation of errant signaling along the MAPK pathway through the inhibition of B-RAF kinase is a validated approach for the treatment of pathway-dependent cancers. We report the development of imidazo-benzimidazoles as potent B-RAF inhibitors. Robust in vivo efficacy coupled with correlating pharmacokinetic/pharmacodynamic (PKPD) and PD-efficacy relationships led to the identification of RAF265, 1, which has advanced into clinical trials.
RESUMO
Two scaffolds based on 5,6-fused heterocyclic backbones were designed and synthesized as Raf kinase inhibitors. The scaffolds were assessed for in vitro pan-Raf inhibition, activity in cell proliferation and target modulation assays, and pharmacokinetic parameters.
Assuntos
Amidas/síntese química , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos/síntese química , Quinases raf/antagonistas & inibidores , Amidas/química , Amidas/farmacologia , Sítios de Ligação , Proliferação de Células , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of arylaminobenzimidazoles was designed and synthesized as Raf kinase inhibitors. Exploration of the structure-activity relationship resulted in compounds that are potent in vitro and show desirable in vivo properties.
Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Quinases raf/antagonistas & inibidores , Administração Oral , Animais , Benzimidazóis/administração & dosagem , Benzimidazóis/química , Disponibilidade Biológica , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Estrutura Terciária de Proteína , Estereoisomerismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases raf/metabolismoRESUMO
The previously unknown stereoisomers 3, 4, ent-1, and ent-4 of the tris(pyrrolidinoindoline) alkaloids hodgkinsine (1) and hodgkinsine B (2) were prepared by stereocontrolled total synthesis. In each synthesis, a catalyst-controlled intramolecular Heck reaction was the key step in appending a third cis-pyrrolidinoindoline ring to a hexacyclic chimonanthine precursor. Results of the preliminary evaluation of these hodgkinsine stereoisomers in the tail flick and capsaicin pain models are reported.
