Small Molecule Disruptors of the Glucokinase–GlucokinaseRegulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, OptimizationThrough Conformational Analysis.

Theglucokinase–glucokinase regulatory protein (GK-GKRP)complex plays an important role in controlling glucose homeostasisin the liver. We have recently disclosed a series of arylpiperazinesas in vitro and in vivo disruptors of the GK-GKRP complex with efficacyin rodent models of type 2 diabetes mellitus (T2DM). Herein, we describea new class of aryl sulfones as disruptors of the GK-GKRP complex,where the central piperazine scaffold has been replaced by an aromaticgroup. Conformational analysis and exploration of the structure–activityrelationships of this new class of compounds led to the identificationof potent GK-GKRP disruptors. Further optimization of this novel seriesdelivered thiazole sulfone 93, which was able to disruptthe GK-GKRP interaction in vitro and in vivo and, by doing so, increasescytoplasmic levels of unbound GK. [ABSTRACT FROM AUTHOR]