Novel heteroaryl-containing benzamide derivatives were synthesized and screened using an in vitro assay measuring increases in glucose uptake and glucokinase activity stimulated by 10mM glucose in rat hepatocytes. From a library of synthesized compounds, 3-(4-methanesulfonylphenoxy)-N-[1-(2-methoxy-ethoxymethyl)-1H-pyrazol-3-yl]-5-(3-methyl pyridin-2-yl)-benzamide (19e) was identified as a potent glucokinase activator with assays demonstrating an EC50 of 315nM and the induction of a 2.23 fold increase in glucose uptake. Compound 19e exhibited a glucose AUC reduction of 32% (50mg/kg) in an OGTT study with C57BL/6J mice compared to 28% for metformin (300mg/kg). Single treatment of the compound in C57BL/J6 and ob/ob mice elicited basal glucose lowering activity, while in a two-week repeated dose study with ob/ob mice, the compound significantly decreased blood glucose levels with no evidence of hypoglycemia risk. In addition, 19e exhibited favorable pharmacokinetic parameters in mice and rats and excellent safety margins in liver and testicular toxicity studies. Compound 19e was therefore selected as a development candidate for the potential treatment of type 2 diabetes.
Keywords: Glucokinase activator (GKA); Type 2 diabetes mellitus (T2DM).
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