Journal of medicinal chemistry · 2022
A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor.
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Griffith David A, Edmonds David J, Fortin Jean-Philippe, Kalgutkar Amit S, Kuzmiski J Brent, Loria Paula M, Saxena Aditi R, Bagley Scott W, Buckeridge Clare, Curto John M, Derksen David R, Dias João M, Griffor Matthew C, Han Seungil, Jackson V Margaret, Landis Margaret S, Lettiere Daniel, Limberakis Chris, Liu Yuhang, Mathiowetz Alan M, Patel Jayesh C, Piotrowski David W, Price David A, Ruggeri Roger B, Tess David A
Аннотация
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.