Amgen has maintained a long-term interest in the role of glucokinase (GK) in the treatment of metabolic disease, culminating in the discovery of a novel binding pocket in the glucokinase regulatory protein (GKRP) and the first reported small molecule inhibitors of the GK-GKRP interaction.1  Subsequent screening and medicinal chemistry efforts have given rise to yet additional inhibitor classes. Early leads in a novel scaffold were complicated by high metabolic turnover. This presentation describes the role of computational techniques in addressing a severe potency-stability conundrum, by incorporation of an unconventional, syn-locked interaction between two adjacent rings. Quantum mechanical calculations were employed to characterize stabilizing interactions and conformational preferences, guiding the design of improved analogs in the series. This strategy resulted in a highly potent and stable modified series, ultimately paving the way for highly in vivo efficacious inhibitors of GK-GKRP.1. http://www.nature.com/nature/journal/v504/n7480/full/nature12724.html

Use of non-traditional conformational restriction in the design of a novel, potent, and metabolically stable series of GK-GKRP inhibitors

248th National Meeting (2014)

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