RESUMO
Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound 1, a glucokinase activator (GKA) lead that we have previously disclosed, caused reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, 2. Subsequent SAR studies of 1 led to the identification of a pyrazine-based lead analogue 3, lacking the thiazole moiety. In vivo metabolite identification studies, followed by the independent synthesis and profiling of the cyclopentyl keto- and hydroxyl- metabolites of 3, led to the selection of piragliatin, 4, as the clinical lead. Piragliatin was found to lower pre- and postprandial glucose levels, improve the insulin secretory profile, increase ß-cell sensitivity to glucose, and decrease hepatic glucose output in patients with T2D.
Assuntos
Benzenoacetamidas/síntese química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ativadores de Enzimas/síntese química , Glucoquinase/metabolismo , Hipoglicemiantes/síntese química , Animais , Benzenoacetamidas/farmacocinética , Benzenoacetamidas/farmacologia , Cães , Ativadores de Enzimas/farmacocinética , Ativadores de Enzimas/farmacologia , Feminino , Glucose/metabolismo , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Lipidoses/metabolismo , Fígado/metabolismo , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Período Pós-Prandial , Coelhos , Ratos , Ratos Wistar , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The phenylacetamide 1 represents the archtypical glucokinase activator (GKA) in which only the R-isomer is active. In order to probe whether the chiral center could be replaced, we prepared a series of olefins 2 and show in the present work that these compounds represent a new class of GKAs. Surprisingly, the SAR of the new series paralleled that of the saturated derivatives with the exception that there was greater tolerance for larger alkyl and cycloalkyl groups at R(2) region in comparison to the phenylacetamides. In normal Wistar rats, the 2,3-disubstituted acrylamide analog 10 was well absorbed and demonstrated robust glucose lowering effects.
Assuntos
Acrilamidas/química , Benzenoacetamidas/química , Glucoquinase/química , Hipoglicemiantes/química , Sulfonas/química , Acrilamidas/síntese química , Acrilamidas/farmacocinética , Animais , Benzenoacetamidas/síntese química , Benzenoacetamidas/farmacocinética , Glucoquinase/metabolismo , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/farmacocinéticaRESUMO
Glucokinase (GK) plays a key role in whole-body glucose homeostasis by catalyzing the phosphorylation of glucose in cells that express this enzyme, such as pancreatic beta cells and hepatocytes. We describe a class of antidiabetic agents that act as nonessential, mixed-type GK activators (GKAs) that increase the glucose affinity and maximum velocity (Vmax) of GK. GKAs augment both hepatic glucose metabolism and glucose-induced insulin secretion from isolated rodent pancreatic islets, consistent with the expression and function of GK in both cell types. In several rodent models of type 2 diabetes mellitus, GKAs lowered blood glucose levels, improved the results of glucose tolerance tests, and increased hepatic glucose uptake. These findings may lead to the development of new drug therapies for diabetes.
