Identification of a novel conformationally constrained glucagon receptor antagonist

Identification of orally active, small molecule antagonists of the glucagon receptor represents a novel treatment paradigm for the management of type 2 diabetes mellitus. The present work discloses novel glucagon receptor antagonists, identified via conformational constraint of current existing literature antagonists. Optimization of lipophilic ligand efficiency (LLE or LipE) culminated in enantiomers (+)-trans-26 and (� )-trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles. In vivo, significant pharmacokinetic differences were noted with the two enantiomers, which were primarily driven through differences in clearance rates. Enantioselective oxidation by cytochrome P450 was ruled out as a causative factor for pharmacokinetic differences. 2014 Elsevier Ltd. All rights reserved. Type 2 Diabetes Mellitus (T2DM), a chronic disease prevalent worldwide, is characterized by impaired insulin secretion and insulin resistance in muscle and liver, resulting in higher blood glucose levels. As insulin resistance and the resulting hyperinsulinemia worsen over time, patients eventually experience b-cell failure. Despite the existence of several therapies, there remains a need to identify novel mechanisms of restoring glucose homeostasis. 1 Glucagon is a 29-amino acid peptide secreted in the a-cells of the pancreas that binds to the glucagon receptor in the liver to modulate hepatic glycogenolysis and gluconeogenesis. Blockade of the glucagon receptor has been proposed as an avenue to reduce hepatic glucose output, thus enabling improved glycemic control. 2