RESUMO
5-HT2C agonists have shown efficacy in limiting food consumption and thus may serve as an important drug class in combating obesity. We describe the design and synthesis of a novel tricyclic single-nitrogen scaffold that was used to produce 5-HT2C agonists. SAR was developed around this chemotype and compounds were identified that were potent (Ki<15 nM) and selective relative to other 5-HT2 receptors. The most promising compound displayed a good pharmacokinetic profile in multiple animal species, and was efficacious in an acute feeding study in rats.
Assuntos
Nitrogênio/química , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/síntese química , Agonistas do Receptor de Serotonina/farmacologia , Animais , Cães , Desenho de Fármacos , Comportamento Alimentar/efeitos dos fármacos , Meia-Vida , Ratos , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacocinética , Relação Estrutura-AtividadeRESUMO
The 5-HT2C receptor has been implicated in the regulation of appetite. As such, small molecule agonists to this receptor may serve as novel therapies to combat obesity. We describe here the identification, synthesis, and SAR of a 5-HT2C agonist from a unique pyrimidine-diazabicyclo[3.3.0]octane series. This compound displayed good potency at the 5-HT2C receptor, modest selectivity relative to other 5-HT2 receptors, and was efficacious in an acute feeding study in rats.