RESUMEN
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.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Piperidinas/síntesis química , Piperidinas/farmacología , Tiazoles/síntesis química , Tiazoles/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Perros , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Inhibidores Enzimáticos/química , Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Piperidinas/química , Ratas , Relación Estructura-Actividad , Tiazoles/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Piridinas/síntesis química , Piridinas/farmacología , Animales , Inhibidores Enzimáticos/química , Histona Desacetilasas/metabolismo , Humanos , Estructura Molecular , Piridinas/química , Ratas , Relación Estructura-ActividadRESUMEN
A new class of small-molecule GnRH antagonists, the thieno[2,3-b]pyrroles, was designed. Herein, the synthesis and structure-activity relationships are described. Substitution at the C4 position was investigated; during this study, it was observed that introducing piperazines and piperidines improved the physical properties of the compounds while retaining good in vitro potency. This exploration led to the discovery of amidopiperidines with improved pharmacokinetic properties.