RESUMO
A series of substituted chromones were designed, synthesized, and evaluated for their ability to bind melanin-concentrating hormone receptor 1. Compounds with subnanomolar binding affinity and 66% oral bioavailability in rats were discovered.
Assuntos
Química Farmacêutica/métodos , Cromonas/síntese química , Melaninas/química , Quinolonas/síntese química , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Receptores do Hormônio Hipofisário/química , Administração Oral , Animais , Cromonas/química , Desenho de Fármacos , Humanos , Microssomos Hepáticos/metabolismo , Modelos Químicos , Quinolonas/química , Ratos , Fatores de TempoRESUMO
Melanin-concentrating hormone receptor antagonists containing thieno- and a benzopyridazinone cores were designed and tested as potential anorectic agents. These ligands showed high affinity for the receptor, potent functional activity in vitro, and good oral bioavailabilty in rats. The thiophene analogue exhibited low iv clearance, long half-life, and high brain penetration. In obese rats, the thienopyridazinone demonstrated a dose-dependent reduction in feeding and body weight with doses between 1 and 10 mg kg-1.