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.

Graphical abstractThe continued discovery of a novel series of pyridine acid containing glucokinase activators is described. The composite parameter of unbound clearance was used to aid in the identification of GKA60, a potent, soluble glucokinase activator with excellent bioavailability and increased half-life.Figure optionsDownload full-size imageDownload as PowerPoint slide