Lotiglipron

Lotiglipron (PF-07081532) is an orally administered, nonpeptide, small-molecule agonist of the human glucagon-like peptide-1 receptor (GLP-1R) developed by Pfizer in collaboration with Sosei Heptares. The compound was designed through structure-based drug design leveraging Sosei Heptares proprietary StaR (stabilized receptor) technology platform, which enables crystallographic resolution of G-protein-coupled receptor conformations that are otherwise too unstable for conventional structural characterization. Lotiglipron binds within the transmembrane domain of the GLP-1R, activating the Gs-coupled adenylyl cyclase signaling cascade and increasing intracellular cyclic adenosine monophosphate (cAMP) in a manner functionally analogous to the endogenous incretin peptide GLP-1(7-36)amide but with the pharmacokinetic advantages of oral bioavailability, once-daily dosing without fasting requirements, and a plasma elimination half-life of approximately 21 to 27 hours that supports sustained receptor engagement across the dosing interval.

The compound entered clinical development in 2021 and was advanced through two Phase 1 multiple-ascending-dose studies (Buckeridge et al. 2024) in 74 participants with type 2 diabetes mellitus (T2D) and 26 participants with obesity without diabetes, demonstrating dose-proportional pharmacokinetics across a 10 to 180 mg once-daily dose range, dose-dependent reductions in glycated hemoglobin (HbA1c) of up to 1.61 percentage points at the 180 mg dose over 42 days, and a safety and tolerability profile consistent with the GLP-1R agonist mechanism class. These findings supported advancement to a Phase 2 dose-ranging study (Amin et al. 2025) in 901 participants (512 with T2D, 389 with obesity), which demonstrated statistically significant reductions in HbA1c of up to 1.44 percentage points (80 mg dose, 16 weeks) and body weight reductions of up to 7.47 percent (200 mg dose, 20 weeks). The Phase 2 study included an open-label semaglutide 14 mg comparator arm; lotiglipron at doses above 20 mg produced HbA1c reductions numerically comparable to or exceeding semaglutide at week 16. However, the Phase 2 study was terminated early following identification of hepatic transaminase elevations (alanine aminotransferase and/or aspartate aminotransferase greater than 3 times the upper limit of normal) in 6.0 to 6.6 percent of lotiglipron-treated participants versus 1.6 percent on placebo, with some individuals reaching elevations greater than 8 times the upper limit of normal. No cases of liver failure, symptomatic hepatitis, or Hy's law were reported. In June 2023, Pfizer announced discontinuation of the lotiglipron clinical program based on the transaminase signal, pharmacokinetic data from Phase 1 drug-drug-interaction studies suggesting impaired hepatic drug transport or metabolism in a subset of participants, and the inability to prospectively identify at-risk individuals.

Lotiglipron is structurally characterized as a benzimidazole-piperidinyl-benzodioxole derivative bearing a chloropyridinyl substituent and an oxetanylmethyl group (molecular formula C31H31ClN4O5, molecular weight 575.05 g/mol as free base; CAS 2401892-75-7). The compound is not approved in any jurisdiction and is not in active clinical development. Research-grade lotiglipron is available from multiple chemical suppliers and remains a tool compound for the investigation of small-molecule GLP-1R agonist pharmacology, biased signaling, and hepatic metabolism of the oral GLP-1R agonist class. This monograph reviews the chemistry, synthesis, receptor pharmacology, pharmacokinetics, preclinical and clinical evidence, sourcing and handling, stack interactions, adverse events, and a comparative assessment against five oral or nonpeptide GLP-1R agonist candidates on five competency standards.