A small-molecule oral agonist of the human glucagon-like peptide-1 receptor

Published on Sep 30, 2020in bioRxiv
· DOI :10.1101/2020.09.29.319483
David A. Griffith73
Estimated H-index: 73
(Pfizer),
David J. Edmonds25
Estimated H-index: 25
(Pfizer)
+ 21 AuthorsDavid A. Tess17
Estimated H-index: 17
(Pfizer)
Sources
Abstract
Abstract Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited by the requirement for injection. Here we describe the first effective, orally bioavailable small molecule GLP-1R agonists. A sensitized high-throughput screen identified a series of small molecule GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nM potency. These small molecule agonists increased insulin levels in primates but not rodents, which is explained by a cryo-EM structure that revealed a binding pocket requiring primate-specific tryptophan 33. Importantly, oral administration of agonist PF-06882961 to healthy humans produced dose-dependent declines in serum glucose (NCT03309241). This opens the door to a new era of oral small molecule therapies that target the well-validated GLP-1R pathway for metabolic health. One Sentence Summary PF-06882961 is an orally administered small molecule that activates the GLP-1 receptor to lower blood glucose in humans.
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