Journal of medicinal chemistryJun 1, 2022

A small oral drug that activates the human GLP-1 receptor

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Apr 1, 2026

Abstract

The orally bioavailable agonist PF-06882961 (danuglipron) demonstrates dose-proportional increases in systemic exposure in healthy humans.

Danuglipron was identified as a small-molecule agonist with nanomolar potency for the glucagon-like peptide-1 receptor (GLP-1R).
In primates, danuglipron increased insulin levels, which was not observed in rodents.
A cryogenic electron microscope structure revealed a binding pocket that requires a primate-specific tryptophan 33 residue.
The incorporation of a carboxylic acid moiety improved GLP-1R potency, off-target pharmacology, and reduced metabolic clearance.

Simplified

Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe the discovery of the orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nanomolar potency. Incorporation of a carboxylic acid moiety provided considerable GLP-1R potency gains with improved off-target pharmacology and reduced metabolic clearance, ultimately resulting in the identification of danuglipron. Danuglipron increased insulin levels in primates but not rodents, which was explained by receptor mutagensis studies and a cryogenic electron microscope structure that revealed a binding pocket requiring a primate-specific tryptophan 33 residue. Oral administration of danuglipron to healthy humans produced dose-proportional increases in systemic exposure (NCT03309241). This opens an opportunity for oral small-molecule therapies that target the well-validated GLP-1R for metabolic health.

Key numbers

N/A

Increase in Insulin Secretion

Observed in primates after danuglipron administration.

25 Participants

Involved in the randomized, double-blind, placebo-controlled study.

300 mg

Given to participants under fasted conditions.

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Funding

Competing interests

The authors declare the following competing financial interest(s): A.S.K., A.M.M., M.C.G., J.M.D., C.B., C.L., S.W.B., D.L., P.M.L., D.R.D., J.M.C., J.-P.F., Y.L., A.R.S., D.A.T., D.W.P., S.H., M.S.L., and D.A.G. are employees and stockholders of Pfizer Inc. J.B.K., D.J.E., R.B.R., D.A.P., and V.M.J. are stockholders of Pfizer Inc. J.C.P. is an employee and stockholder of Sosei Heptares.

PubMed

A small oral drug that activates the human GLP-1 receptor

Abstract

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Competing interests

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Abstract

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Competing interests

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