939-P: HD-7671, a Nonpeptide Small Molecule for Orally Available GLP-1 Receptor Agonist, Improves Glucose Tolerance by Increasing Insulin Secretion

Abstract

Glucagon-like peptide-1 (GLP-1) mediates antidiabetogenic effects through the GLP-1 receptor (GLP-1R), which is targeted for the treatment of type 2 diabetes. Currently, GLP-1R agonists comprise a growing class of agents that deliver unprecedented efficacy in diabetes. We discovered a new small molecule GLP-1R agonist, HD-7671, and examined its efficacy in cynomolgus monkeys. The in vitro potency of HD-7671 was evaluated by measuring cAMP accumulation in cells with stable expression of human GLP-1R. HD-7671 stimulated cAMP accumulation and its EC50 value was 2.0 nM. In the cells transfected with human or cynomolgus monkey GLP-1R, HD-7671 promoted cAMP accumulation and its EC50 values for human and cynomolgus monkey GLP-1Rs were 4.5 nM and 7.1 nM, respectively. In contrast, HD-7671 showed no stimulatory activity on other animal species GLP-1Rs. In pharmacokinetic properties, the elimination half-life following oral administration(T1/2) was 0.99 hr in rats and 5.62 hr in cyno monkeys and Cmax was 10,183 ng/ml in rats and 1,423 ng/ml at 10mg/kg, respectively. To evaluate the in vivo insulinotropic effects of HD-7671, glucose stimulated insulin secretion was measured in compound treated in cyno monkeys undergoing an IVGTT. HD-7671 (dosed at 10mg/kg) decreased the blood glucose level and increased insulin secretion. These results demonstrate that HD-7671 has full agonistic activity on human and cynomolgus GLP-1R and improves glucose tolerance by stimulating insulin secretion.