John Wall Rayner

Design of a potent, soluble glucokinase activator with increased pharmacokinetic half-life.

The continued optimization of a series of glucokinase activators is described, including attempts to understand the interplay between molecular structure and the composite parameter of unbound clearance. These studies resulted in the discovery of a new scaffold for glucokinase activators and further exploration of this scaffold led to the identification of GKA60. GKA60 maintains an excellent balance of potency and physical properties whilst possessing a significantly different, but complimentary, pre-clinical pharmacokinetic profile compared with the previously disclosed compound GKA50.

Property based optimisation of glucokinase activators – discovery of the phase IIb clinical candidate AZD1656

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.