Novel Orforglipron analogs 17-P1 and 24-P1 achieve superior oral pharmacokinetics and potency

Orforglipron (OFG) is a leading oral small-molecule GLP-1R agonist for metabolic diseases like type 2 diabetes and obesity. While effective, its oral exposure plateaus at higher doses, potentially limiting therapeutic efficacy and requiring ongoing administration. This limitation highlights a critical gap in achieving optimal and sustained therapeutic benefits from oral GLP-1R agonists, necessitating the development of compounds with enhanced pharmacokinetic profiles.

Researchers systematically modified the solvent-exposed 4-fluoro-1-methylindazole branch of Orforglipron to improve its physicochemical and pharmacokinetic properties. They synthesized and evaluated novel compounds, including 17-P1 and 24-P1, for human GLP-1R agonistic activity (EC50), Caco-2 permeability, and oral bioavailability in mice. In vivo efficacy was assessed by measuring glucose-lowering and food-intake-suppressing effects in unspecified mouse models.

Both 17-P1 and 24-P1 exhibited potent human GLP-1R agonistic activity, with EC50 values of 0.64 nM and 0.53 nM, respectively, demonstrating subnanomolar potency comparable to or better than Orforglipron. Oral bioavailability in mice was dramatically improved for the new compounds: 17-P1 achieved 54.0% and 24-P1 reached 72.4%, a significant increase compared to Orforglipron's 6.4%. Caco-2 permeability also saw marked improvement, with 17-P1 at 2.83 nm/s and 24-P1 at 4.75 nm/s, compared to Orforglipron's 0.14 nm/s. In vivo, these novel compounds produced robust glucose-lowering and food-intake-suppressing effects. This indicates that modification at the 4-fluoro-1-methylindazole site is an effective strategy to enhance oral pharmacokinetics without compromising potency.

Oral bioavailability in mice for 17-P1 and 24-P1 was 8.4-fold and 11.3-fold higher, respectively, than Orforglipron.