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

Autor:	Griffith DA; Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States., Edmonds DJ; Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States., Fortin JP; Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States., Kalgutkar AS; Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States., Kuzmiski JB; Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States., Loria PM; Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States., Saxena AR; Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States., Bagley SW; Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States., Buckeridge C; Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States., Curto JM; Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States., Derksen DR; Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States., Dias JM; Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States., Griffor MC; Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States., Han S; Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States., Jackson VM; Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States., Landis MS; Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States., Lettiere D; Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States., Limberakis C; Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States., Liu Y; Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States., Mathiowetz AM; Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States., Patel JC; Sosei Heptares, Cambridge CB21 6DG, U.K., Piotrowski DW; Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States., Price DA; Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States., Ruggeri RB; Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States., Tess DA; Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2022 Jun 23; Vol. 65 (12), pp. 8208-8226. Date of Electronic Publication: 2022 Jun 01.
DOI:	10.1021/acs.jmedchem.1c01856
Abstrakt:	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.
Databáze:	MEDLINE
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