A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor

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.

Automated summary

Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have been a breakthrough in diabetes therapy, but their use is limited due to the need for injection. In this study, a small-molecule GLP-1R agonist, danuglipron, was discovered that can be taken orally. Danuglipron showed the ability to promote GLP-1R signaling and increase insulin levels in primates, but not in rodents. This discovery opens up the possibility of oral small-molecule therapies targeting the validated GLP-1R for metabolic health.