Amgen, Inc. has previously disclosed the first orally active compounds that inhibit the GK�GKRP binding interaction by selectively engaging a formerly unknown allosteric binding pocket on GKRP (Nature, 504 , pp 437-440) with additional studies within this arylpiperazine series of compounds having also been recently published (J. Med. Chem., 2014 , 57 (2), pp 309-338). The development of an alternative series of inhibitors began with a modestly potent (�M enzyme IC50) screening hit with high microsomal clearance.  Following computationally-designed coplanarization of neighboring heterocyclic rings, we created a modified series with improved activity and stability properties.  From this new starting point, this presentation will discuss how the further use of X-ray crystallography of compounds bound to GKRP, along with structural alignment to the prior chemical series, and iterative medicinal chemistry design cycles yielded analogs with vastly improved activity (nM IC50 enzyme). In addition, we completed microsomal in vitro metabolite identification studies that aided in the discovery of lead compounds with pharmacokinetic profiles suitable for evaluation in diabetic rodent models.  These new compounds were shown to induce in vivo GK translocation in rats and revealed pharmacodynamic blood glucose reduction in mice. This newly presented series expands the possibility to further explore GK-GKRP as a potential therapeutic target for type II diabetes.

Small molecule inhibitors for glucokinase�glucokinase regulatory protein (GK�GKRP) binding: Optimization for in vivo target assessment of type II diabetes

248th National Meeting (2014)

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