Small molecule glucagon-like peptide-1 receptor agonist AZD0186 was developed to provide accessible and convenient treatment for a broad patient population with type 2 diabetes mellitus and/or obesity. We describe the preclinical and first-in-human single ascending dose data (NCT05694741) for this novel small molecule glucagon-like peptide-1 receptor agonist. AZD0186 was profiled in cell lines overexpressing human or cynomolgus glucagon-like peptide-1 receptor (GLP-1R) and in human-derived EndoC-βH5 cells. Glucose-stimulated insulin secretion (GSIS) was assessed following an intravenous glucose tolerance test in obese nonhuman primates and humanized GLP-1R (hGLP-1R) mice. Effects of oral repeated dosing on body weight and food intake were assessed in hGLP-1R mice. AZD0186 was evaluated at 4 oral single ascending dose levels (5, 15, 50, and 150 mg) in healthy participants. Results showed that AZD0186 is potent on the hGLP-1R and showed a concentration-dependent potentiation of GSIS in EndoC-βH5 cells (EC= 0.6 nM). Insulin secretion was enhanced in obese nonhuman primates at all 3 dose levels evaluated following an intravenous glucose tolerance test. In hGLP-1R mice, body weight was reduced 9.9% ± 2.3% (mean ± SD) following 5 days of oral dosing (25 mg/kg per day twice a day). In the healthy participants, AZD0186 was well tolerated, with nausea reported at 150 mg, in keeping with GLP-1RA class effects. Across the dose range, AZD0186 area under the concentration-time curve increased in an approximately dose-proportional manner. Median terminal half-life ranged from 1.95 to 7.58 hours. Findings demonstrate that AZD0186 is a potent agonist of the GLP-1R, and the first-in-human study indicates a favorable safety and tolerability profile. SIGNIFICANCE STATEMENT: AZD0186 is a novel small molecule glucagon-like peptide-1 receptor agonist that allows for oral dosing. We describe the preclinical and first-in-human single ascending dose data for AZD0186. The findings demonstrate that AZD0186 is a potent agonist of the human glucagon-like peptide-1 receptor, improves glucose control and reduces body weight in a human glucagon-like peptide-1 receptor mouse model, and has a favorable safety and tolerability profile in healthy human participants. 50
