As an alternative approach to glucokinase activators (GKAs) for the management of type 2 diabetes, we focused on compounds that promote the release of glucokinase by disrupting the glucokinase-glucokinase regulatory protein (GK-GKRP) interaction.    These initial investigations led to the development of a series of N-arylsulfonamido-N'-aryl-piperazines and culminated in the identification of AMG-3969, a compound that effectively enhanced GK translocation and reduced blood glucose levels in diabetic animals.  Herein we report the results of our investigations that focus on modifications at the aryl carbinol group of this series.  Guided by structure-based design utilizing an X-ray co-crystal structure of AMG-3969 bound to hGKRP, we identified several potent GK-GKRP disruptors bearing a diverse set of functionalities in the aryl carbinol region such as sulfoximine and pyridinyl derivatives.  The structure-activity relationships, pharmacokinetic data as well as the in vivo pharmacodynamic and efficacy data for representative compounds will be presented.

Structure-activity relationships within the aryl carbinol region of the N-arylsulfonamido-N'-aryl-piperazine series of GK-GKRP disruptors

247th National Meeting (2014)

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