RESUMEN
Novel anthranilamides were surprisingly found to exert additional activity on B-RAF. Corresponding thiophene, pyrazole, and thiazole core analogs were prepared as VEGFR-2 inhibitors with c-KIT, and B-RAF activity. Compounds in the phenyl, thiophene, and thiazole series are in vivo active.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Humanos , Ratones , Inhibidores de Proteínas Quinasas/uso terapéutico , Relación Estructura-ActividadRESUMEN
Several imidazole-based cyclohexyl amides were identified as potent CB-1 antagonists, but they exhibited poor oral exposure in rodents. Incorporation of a hydroxyl moiety on the cyclohexyl ring provided a dramatic improvement in oral exposure, together with a ca. 10-fold decrease in potency. Further optimization provided the imidazole 2-hydroxy-cyclohexyl amide 45, which exhibited hCB-1 K(i)=3.7nM, and caused significant appetite suppression and robust, dose-dependent reduction of body weight gain in industry-standard rat models.
Asunto(s)
Fármacos Antiobesidad/farmacología , Peso Corporal/efectos de los fármacos , Receptor Cannabinoide CB1/antagonistas & inhibidores , Animales , Fármacos Antiobesidad/uso terapéutico , Relación Dosis-Respuesta a Droga , Imidazoles/farmacología , Imidazoles/uso terapéutico , Obesidad/tratamiento farmacológico , Ratas , Ratas Zucker , Receptores de Cannabinoides/metabolismo , Relación Estructura-ActividadRESUMEN
A series of (5-(2H)-isoxazolonyl) ureas were developed as nanomolar inhibitors of hormone-sensitive lipase, an enzyme of potential importance in the treatment of diabetes.
