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. In conclusion, HD-7671 has potential as an orally active, non-peptide GLP-1R agonist for the treatment of type 2 diabetes. Disclosure M. Baek: None. D. Kim: None. C. Kim: Employee; Self; Hyundai Pharmaceutical Co., Ltd. D. Kim: Employee; Self; Hyundai Pharm. H. Choi: Employee; Self; Hyundai Pharm. corp. S. Kang: Employee; Self; Hyundai pharm.corp. H. Lee: Employee; Self; Hyundai Pharm. K. Lee: Employee; Self; Hyundai Pharm.

New Insights into the Structure and Function of Class B1 GPCRs

“…Numerous pharmacokinetically improved analogs of GLP-1 have been successfully developed as therapeutics for T2DM and obesity ( 233 ), and many other exploratory peptide agonists have been synthesized to interrogate GLP-1R function ( 210 , 234 ). In addition, there are increasing numbers of small molecule agonists that have been identified ( 235–237 ), with 4 series undergoing clinical evaluation, including PF-06882961, PF-07081532, TTP-273 and OWL-833 ( 238–240 ). Thus, as a pleiotropically coupled receptor that can be activated by numerous ligands, the GLP-1R is disposed to biased agonism and indeed is among the best studied receptors for this phenomenon in both pharmacological and structural aspects.…”

Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening

“…As a successful therapeutic target for type 2 diabetes and obesity, many peptidic analogs of GLP-1 are on the market. Meanwhile, continuous efforts in small-molecule drug discovery resulted in several nonpeptidic agonists such as Boc5 [14], TT-OAD2 [15], PF-06882961 [16], RGT1383 [17] and HD-7671 [18], as well as dozens of small molecule allosteric modulators that interact with distinct regions of GLP-1R. There are at least four reported allosteric sites in class B1 GPCRs including: (i) deep inside the helical bundle observed in the corticotropin-releasing factor receptor type 1 receptor (CRF1R) [19]; (ii) extracellular helical bundle at the TM helices 1 and 2 interface found in GLP-1R [8]; (iii) TM helices 3−4−5 interface with receptor activity-modifying protein 1 (RAMP1) seen in the calcitonin gene related peptide receptor (CGRP) [20]; and (iv) outside of the helical bundle of TM helices 5, 6 and 7 at the lipid interface of GLP-1R and glucagon receptor (GCGR) [7,21].…”