Property based optimisation of glucokinase activators - discovery of the phase IIb clinical candidate AZD1656Electronic supplementary information (ESI) available: Assay protocols, comparison of MDCK and Caco-2 data, tabulated datasets and synthetic details for the compounds described. See DOI: 10.1039/c2md20077e

Glucokinase plays a central role in glucose homeostasis and small molecule activators of the glucokinase enzyme have been the subject of significant pharmaceutical research in the quest for agents capable of delivering improved glycaemic control. Here we describe our medicinal chemistry campaign to improve on our previously described development candidate in this area, AZD1092, focussed on removal of Ames liability and improved permeability characteristics. This work culminated in the superior compound AZD1656 which has progressed to phase 2 clinical trials. Further optimisation of the previously described development candidate AZD1092, focussed on removal of Ames liability and improved permeability characteristics, led to a superior compound AZD1656 which has progressed to phase 2 clinical trials.