anti-diabetic efficacy and impact on amino acid metabolism of gra1, a novel small-molecule glucagon receptor antagonist抗糖尿病疗效和gra1对氨基酸代谢的影响,一种新型小分子胰高血糖素受体拮抗剂.pdfVIP

Anti-Diabetic Efficacy and Impact on Amino Acid Metabolism of GRA1, a Novel Small-Molecule Glucagon Receptor Antagonist James Mu*, Sajjad A. Qureshi, Edward J. Brady, Eric S. Muise, Mari Rios Candelore, Guoqiang Jiang, Zhihua Li, Margaret S. Wu, Xiaodong Yang, Qing Dallas-Yang, Corey Miller, Yusheng Xiong, Ronald B. Langdon, Emma R. Parmee, Bei B. Zhang Discovery and Preclinical Sciences, Merck Research Laboratories, Merck Sharp Dohme Corp., Whitehouse Station, New Jersey, United States of America Abstract Hyperglucagonemia is implicated in the pathophysiology of hyperglycemia. Antagonism of the glucagon receptor (GCGR) thus represents a potential approach to diabetes treatment. Herein we report the characterization of GRA1, a novel small- molecule GCGR antagonist that blocks glucagon binding to the human GCGR (hGCGR) and antagonizes glucagon-induced intracellular accumulation of cAMP with nanomolar potency. GRA1 inhibited glycogenolysis dose-dependently in primary human hepatocytes and in perfused liver from hGCGR mice, a transgenic line of mouse that expresses the hGCGR instead of the murine GCGR. When administered orally to hGCGR mice and rhesus monkeys, GRA1 blocked hyperglycemic responses to exogenous glucagon. In several murine models of diabetes, acute and chronic dosing with GRA1 significantly reduced blood glucose concentrations and moderately increased plasma glucagon and glucagon-like peptide-1. Combination of GRA1 with a dipeptidyl peptidase-4 inhibitor had an additive antihyperglycemic effect in diabetic mice. Hepatic gene- expression profiling in monkeys treated with GRA1 revealed down-regulation of numerous genes involved in amino acid catabolism, an effect that was paralleled by increased amino acid levels in the circulation. In summary, GRA1 is a potent glucagon receptor antagonist with strong antihyperglycemic efficacy in preclinical mod