Danuglipron

Danuglipron (PF-06882961) is an orally bioavailable, non-peptide, small-molecule full agonist of the human glucagon-like peptide-1 receptor (GLP-1R) discovered at Pfizer through a sensitized high-throughput screen of 2.8 million compounds and advanced through Phase 2b clinical development for type 2 diabetes mellitus and obesity before discontinuation in April 2025 following a single case of potential drug-induced liver injury in a dose-optimization study. The compound is a benzimidazole-6-carboxylic acid bearing a piperidine-linked pyridine with a 4-cyano-2-fluorobenzyloxy substituent and an (S)-oxetanylmethyl group (molecular formula C31H30FN5O4; molecular weight 555.61; CAS 2230198-02-2). Danuglipron activates the GLP-1R with nanomolar potency at cAMP accumulation and insulin secretion endpoints in cells expressing human or primate receptor, but is inactive at rodent GLP-1R owing to a species-specific binding pocket that requires tryptophan at position 33 of the receptor extracellular domain (Trp33ECD), a residue that is serine in mouse, rat, and rabbit. A cryogenic electron microscopy structure at 2.5 angstrom resolution (PDB 7S15) revealed that danuglipron binds at the orthosteric peptide-binding site but engages the extracellular domain in a distinct conformation in which the ECD rotates and Trp33 moves approximately 14 angstroms to close the top of the small-molecule binding pocket, a conformational rearrangement not observed with peptide agonists. The compound signals through canonical Gs-coupled cAMP production, beta-arrestin recruitment, and receptor internalization pathways in a manner broadly similar to the endogenous peptide GLP-1(7-36)amide, and is therefore classified as an approximately unbiased full agonist at the receptor level, in contrast to the partial-agonist, Gs-biased profile of the competing small-molecule candidate orforglipron. Pharmacokinetics in humans are characterized by rapid oral absorption with minimal food effect, a terminal elimination half-life of approximately 5 to 6 hours supporting dosing for the immediate-release formulation, hepatic clearance predominantly through CYP3A4-mediated oxidative metabolism, hepatic uptake via organic anion-transporting polypeptide transporters OATP1B1, OATP1B3, and OATP2B1, and negligible renal excretion of unchanged drug. In the Phase 1 multiple ascending-dose trial in 98 patients with type 2 diabetes (Saxena et al. 2021, Nature Medicine), danuglipron produced dose-dependent reductions in fasting and postprandial glucose with tolerability limited principally by gastrointestinal adverse events (nausea, vomiting, dyspepsia). In the Phase 2 randomized trial in 411 patients with type 2 diabetes (Saxena et al. 2023, JAMA Network Open), the 120 mg dose produced a placebo-adjusted HbA1c reduction of 1.16 percentage points, a fasting plasma glucose reduction of 33.24 mg/dL, and clinically meaningful body weight reduction over 16 weeks. In the Phase 2b obesity trial (Buckeridge et al. 2025, Diabetes, Obesity and Metabolism), placebo-adjusted body weight reductions ranged from 5.0 to 12.9 percent at 26 to 32 weeks, with discontinuation rates exceeding 50 percent across all dose groups principally due to gastrointestinal adverse events. Pfizer discontinued danuglipron development in December 2023 due to tolerability concerns and advanced a modified-release formulation that met pharmacokinetic objectives in dose-optimization studies; however, in April 2025, a single asymptomatic case of potential drug-induced liver injury in a dose-optimization study, combined with a comprehensive portfolio review and regulatory input, led Pfizer to discontinue all danuglipron development. The compound is not approved in any jurisdiction. It is available as a research-grade preparation from multiple chemical suppliers and serves as a critical reference compound for the emerging class of non-peptide oral GLP-1R agonists.