<br/>The intracellular enzyme glucokinase (GK) is expressed primarily in liver and pancreas. GK facilitates the conversion of glucose to glucose-6-phosphate – the first step in glucose metabolism – and is a key regulator of glucose homeostasis. Small molecule allosteric activators of GK have been demonstrated in numerous animal models and clinical trials to lower glucose levels – thereby showing therapeutic promise for the treatment glucose metabolism disorders. However, it has been postulated that GK activation in pancreatic beta-cells, even at low glucose concentrations, may result in excessive insulin secretion and ultimately, mechanism-based hypoglycemia. To ameliorate the potential for hypoglycemia, hepatocentric GK activators based on 5-amido-1,2,4-thiadiazoles have been developed. Described herein is the design and SAR of several potent, liver-centric GK activators with excellent oral exposure and liver selectivity in mouse PK studies. Despite achieving high drug liver concentrations and having suitable protein free fraction, these GK activators did not show efficacy in mouse PD studies. Efforts are ongoing to understand this PK / PD disconnect.

Thiadiazole analogues as potent, liver selective glucokinase activators

2019 Fall National Meeting

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