RESUMEN
Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays a role in metabolic and CNS disorders. The modeling-supported design, synthesis and multi-parameter optimization (biological activity, solubility, metabolic stability, hERG) of novel quinazoline derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. Clusters of refined hMCHR1 homology models derived from the X-ray structure of the ß2-adrenergic receptor, including extracellular loops, were developed and used to guide the design.
Asunto(s)
Diseño de Fármacos , Quinazolinas/síntesis química , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Humanos , Estructura Molecular , Quinazolinas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
Melanin concentrating hormone receptor 1 (MCHR1) antagonists have potential for the treatment of obesity and several CNS disorders. In the preceding article, we have described a novel series of quinazolines as MCHR1 antagonists and demonstrated in vivo proof of principle with an early lead. Herein we describe the detailed SAR and SPR studies to identify an optimized lead candidate having good efficacy in a sub-chronic DIO model with a good cardiovascular safety window.
Asunto(s)
Diseño de Fármacos , Quinazolinas/síntesis química , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Enfermedades Cardiovasculares/prevención & control , Humanos , Quinazolinas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
The synthesis and biological evaluation of novel pyrazole-3-carboxamide derivatives as CB1 antagonists are described. As a part of eastern amide SAR, various chemically diverse motifs were introduced. In general, a range of modifications were well tolerated. Several molecules with high polar surface area were also identified as potent CB1 receptor antagonists. The in vivo proof of principle for weight loss is exemplified with a lead compound from this series.
Asunto(s)
Amidas/química , Pirazoles/química , Receptor Cannabinoide CB1/antagonistas & inhibidores , Tetrazoles/química , Administración Oral , Amidas/síntesis química , Amidas/farmacología , Animales , Ratones , Pirazoles/síntesis química , Pirazoles/farmacología , Ratas , Receptor Cannabinoide CB1/metabolismo , Relación Estructura-Actividad , Tetrazoles/síntesis química , Tetrazoles/farmacología , Pérdida de Peso/efectos de los fármacosRESUMEN
The synthesis and biological evaluation of novel pyrazole and imidazole carboxamides as CB1 antagonists are described. As a part of eastern amide SAR, various chemically diverse motifs were introduced on rimonabant template. The central pyrazole core was also replaced with its conformationally constrained motif and imidazole moieties. In general, a range of modifications were well tolerated. Several molecules with low- and sub-nanomolar potencies were identified as potent CB1 receptor antagonists. The in vivo proof of principle for weight loss is demonstrated with a lead compound in DIO mice model.