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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][1]). 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. ### Competing Interest Statement ASK, AMM, MCG, JMD, CB, CL, SWB, DJL, PML, DRD, JMC, JPF, YL, ARS, DAT, DWP, SH, RBR, MSL, and DAG are employees and stockholders of Pfizer Inc. DAP, DJE, JBK and VMJ are stockholders of Pfizer Inc. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03309241&atom=%2Fbiorxiv%2Fearly%2F2020%2F09%2F30%2F2020.09.29.319483.atom

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