Blood glucose levels are maintained by the balance of glucose production in the liver and glucose uptake in peripheral tissues. An inappropriately high rate of hepatic glucose production (HGP) is the predominant cause of fasting hyperglycemia and a major contributor to the postprandial hyperglycemia characteristic of type 2 diabetes (T2DM). The glucagon receptor is predominantly located in the liver and upon activation stimulates hepatic glycogenolysis and gluconeogenesis. Studies in T2DM patients have demonstrated a causal role for glucagon in promoting excessive HGP. Glucagon receptor antagonists (GRAs) therefore have the potential to reduce HGP and be effective anti-diabetic agents.This presentation will describe the synthesis and biological evaluation of a novel series of GRAs bearing an ether linkage, designed based on an earlier GRA lead MK-3577.

Novel glucagon receptor antagonists bearing an ether linkage for the treatment of type II diabetes

248th National Meeting (2014)

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