Discovery of Small-Molecule GLP-1 Receptor Agonists with Improved Oral Pharmacokinetics Based on Orforglipron

Orforglipron is a leading oral small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist for metabolic diseases; however, its oral exposure plateaus at higher doses, potentially limiting therapeutic efficacy. The solvent-exposed 4-fluoro-1-methylindazole branch of orforglipron was identified as a site amenable to modification for improving the physicochemical and pharmacokinetic properties. Systematic structure–activity relationship studies demonstrated that this region is highly tolerant of ring closure and expansion, yielding compounds 17-P1 and 24-P1 with subnanomolar hGLP-1R agonistic activity (EC50 = 0.64 and 0.53 nM, respectively). Compared with orforglipron, both compounds exhibited markedly improved permeability (Caco-2 Papp = 2.83 and 4.75 nm/s vs 0.14 nm/s) and enhanced oral bioavailability in mice (54.0% and 72.4% vs 6.4%). In vivo, 17-P1 and 24-P1 produced robust glucose-lowering and food-intake-suppressing effects. Collectively, modification at the 4-fluoro-1-methylindazole site defines an effective strategy to enhance oral pharmacokinetics without compromising potency, providing a foundation for further optimization.