Glucokinase (GK) is a hexokinase that catalyzes the reaction from glucose to glucose 6-phosphate. It also works as a glucose sensor and plays a key role in glucose homeostasis in humans. Physiologically, glucokinase is localized mainly in the liver, pancreas and brain. Systemically acting glucokinase activators have been demonstrated in clinical trials to effectively lower blood glucose levels in type II diabetic patients. However, hypoglycemia has also been found to be a potential risk factor that can limit the therapeutic application of this mechanism. Presumably, if the hypoglycemia risk is caused by pancreatic insulin secretion at low glucose level trigged by the activation of GK in beta cells, restricted activation of GK in hepatocytes may offer a promising solution to the issue. Herein, we report the discovery of a novel series of carboxylic acid containing GKAs based on pyridine-2-carboxyamide. These GKAs exhibit preferential activity in vitro in hepatocytes versus pancreatic INS1 cells. SAR studies led to the identification of a potent and orally active compound which demonstrated robust glucose lowering efficacy in HFD mice at 10 mpk with over 120-fold liver to pancreas ratio of tissue drug distribution, and no effect on insulin secretion. The design, synthesis, and biological evaluation of these novel GKAs will be discussed.

Discovery of novel pyridine-2-carboxyamides as liver-preferring glucokinase activators for treatment of type II diabetes mellitus

248th National Meeting (2014)

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