RESUMO
Allosteric activators of the glucose-sensing enzyme glucokinase (GK) are currently attracting much interest as potential antidiabetic therapies because they can achieve powerful blood glucose lowering through actions in multiple organs. Here, the optimization of a weakly active high-throughput screening hit to (2 R)-2-(4-cyclopropanesulfonylphenyl)- N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (PSN-GK1), a potent GK activator with an improved pharmacokinetic and safety profile, is described. Following oral administration, this compound elicited robust glucose lowering in rats.
Assuntos
Glucoquinase/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Sulfonas/química , Sulfonas/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Animais , Ativação Enzimática , Feminino , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/enzimologia , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Sulfonas/efeitos adversos , Sulfonas/farmacocinética , Tiazóis/efeitos adversos , Tiazóis/farmacocinéticaRESUMO
The synthesis, SAR and biological evaluation of a series of ureas that activate glucokinase, a target for diabetes therapy as a result of its critical role in the regulation of whole-body glucose homeostasis, are described. Some of the urea-containing glucokinase activators lowered blood glucose levels in vivo following oral dosing to C57BL/6J mice.