Discovery of a Novel Phenylethyl Benzamide Glucokinase Activator for the Treatment of Type 2 Diabetes Mellitus
Bioorganic & medicinal chemistry letters(2013)
摘要
Novel benzamide derivatives were synthesized and tested at in vitro assay by measuring fold increase of glucokinase activity at 5.0 mM glucose concentration. Among the prepared compounds, YH-GKA was found to be an active glucokinase activator with EC(50) of 70 nM. YH-GKA showed similar glucose AUC reduction of 29.6% (50 mg/kg) in an OGTT study with C57BL/J6 mice compared to 29.9% for metformin (300 mg/kg). Acute treatment of the compound in C57BL/J6 and ob/ob mice elicited basal glucose lowering activity. In subchronic study with ob/ob mice, YH-GKA showed significant decrease in blood glucose levels and no adverse effects on serum lipids or body weight. In addition, YH-GKA exhibited high bioavailability and moderate elimination in preclinical species.
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关键词
Glucokinase,Glucokinase activator,GKAs,YH-GKA,T2DM,Type 2 diabetes mellitus,OGTT
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