RESUMO
A novel series of substituted quinoline analogs were designed and synthesized as potent and selective melanin concentrating hormone (MCH) antagonists. These analogs show potent (nM) activity (12a-k) with a moderate selectivity. Conversely, the conformationally constrained thienopyrimidinone analogs (18a-g) showed improved activity in MCH-1R and selectivity over 5HT2C.
Assuntos
Fármacos Antiobesidade/síntese química , Hormônios Hipotalâmicos/antagonistas & inibidores , Melaninas/antagonistas & inibidores , Hormônios Hipofisários/antagonistas & inibidores , Quinolinas/síntese química , Quinolinas/farmacologia , Fármacos Antiobesidade/farmacologia , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Ligantes , Pirimidinonas , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Structure-guided de novo drug design led to the identification of a novel series of substituted pyridine derivatives as HIF-1alpha prolyl hydroxylase inhibitors. Pyridine carboxyamide derivatives bearing a substituted aryl group at the 5-position of the pyridine ring show appreciable activity, while constraining the side chain by placing a pyrazole carboxylic acid generated a potent lead series with consistent activity against EGLN-1.