2. Academic Validation
  3. A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor

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

  • J Med Chem. 2022 Jun 23;65(12):8208-8226. doi: 10.1021/acs.jmedchem.1c01856.
David A Griffith 1,  David J Edmonds 1,  Jean-Philippe Fortin 1,  Amit S Kalgutkar 1,  J Brent Kuzmiski 1,  Paula M Loria 2,  Aditi R Saxena 1,  Scott W Bagley 2,  Clare Buckeridge 1,  John M Curto 2,  David R Derksen 2,  João M Dias 2,  Matthew C Griffor 2,  Seungil Han 2,  V Margaret Jackson 1,  Margaret S Landis 1,  Daniel Lettiere 2,  Chris Limberakis 2,  Yuhang Liu 2,  Alan M Mathiowetz 1,  Jayesh C Patel 3,  David W Piotrowski 2,  David A Price 1,  Roger B Ruggeri 1,  David A Tess 1
Affiliations

Affiliations

  • 1 Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States.
  • 2 Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States.
  • 3 Sosei Heptares, Cambridge CB21 6DG, U.K.
PMID: 35647711 DOI: 10.1021/acs.jmedchem.1c01856
Abstract

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.

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