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
  • 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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