RESUMO
A lead benzamide, 3, was identified as a potent and low molecular weight histone deacetylase (HDAC) inhibitor. Optimization led to 16d, demonstrating an excellent balance of efficacy and non-efficacy properties, along with very desirable in vivo DMPK. The final compounds presented are >1000-fold more potent than the initial screen hit, an improvement in potency which was achieved with a concomitant significant improvement in all the main non-efficacy properties.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Piperidinas/síntese química , Piperidinas/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Cães , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/química , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Piperidinas/química , Ratos , Relação Estrutura-Atividade , Tiazóis/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A lead benzamide, bearing a cyanopyridyl moiety (3), was identified as a potent and low molecular weight histone deacetylase (HDAC) inhibitor. Various replacements of the cyano group were explored at the C3-position, along with the exploration of solubility-enhancing groups at the C5-position. It was determined that cyano substitution at the C3-position of the pyridyl core, along with a methylazetidinyl substituent at the C5-position yielded optimal HDAC1 inhibition and anti-proliferative activity in HCT-116 cells.
