RESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Humanos , Camundongos , Inibidores de Proteínas Quinases/uso terapêutico , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Fármacos Antiobesidade/farmacologia , Peso Corporal/efeitos dos fármacos , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Fármacos Antiobesidade/uso terapêutico , Relação Dose-Resposta a Droga , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Obesidade/tratamento farmacológico , Ratos , Ratos Zucker , Receptores de Canabinoides/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
