Overcoming retinoic acid receptor-α based testicular toxicity in the optimisation of glucokinase activators

Small molecule activators of the glucokinase enzyme have the potential to deliver a level of glycaemic control that is superior to current oral agents and hence have great promise as new therapies for Type 2 Diabetes. As such, attempts to discover glucokinase activators suitable for clinical development have been the focus of many major pharmaceutical research programmes. Here we describe how we have overcome a testicular toxicological liability in our pyridine acid lead series, which we show can be ascribed to antagonism of the retinoic acid receptor-α.