Matrix-based multiparameter optimisation of glucokinase activators: the discovery of AZD1092

Abstract

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 show how property-based matrix optimisation has been used to improve the multi-parameter technical profile of the AstraZeneca series of glucokinase activators culminating in the discovery of the development candidate AZD1092.