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We now report the discovery of LY3502970, a potent and selective small-molecule GLP-1R agonist. LY3502970 exhibits preclinical pharmacology equivalent to a marketed injectable GLP-1R agonist and possesses pharmacokinetic properties compatible with oral dosing in humans. Cryoelectron microscopy (cryo-EM) studies reveal an ECD-driven receptor binding mode for LY3502970 that provides a favorable pharmacological profile.<\/jats:p>","DOI":"10.1073\/pnas.2014879117","type":"journal-article","created":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T19:51:06Z","timestamp":1605124266000},"page":"29959-29967","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":231,"title":["Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist"],"prefix":"10.1073","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5490-9071","authenticated-orcid":false,"given":"Takahiro","family":"Kawai","sequence":"first","affiliation":[{"name":"Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka 412-8513, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingfa","family":"Sun","sequence":"additional","affiliation":[{"name":"ConfometRx, 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