Glucagon-like peptide-1 receptor (GLP-1R) agonists are efficacious antidiabetic medications that work by enhancing glucose-dependent insulin secretion and improving energy balance. Currently approved GLP-1R agonists are peptide based, and it has proven difficult to obtain small-molecule activators possessing optimal pharmaceutical properties. We report the discovery and mechanism of action of LY3502970 (OWL833), a nonpeptide GLP-1R agonist. LY3502970 is a partial agonist, biased toward G protein activation over β-arrestin recruitment at the GLP-1R. The molecule is highly potent and selective against other class B G protein–coupled receptors (GPCRs) with a pharmacokinetic profile favorable for oral administration. A high-resolution structure of LY3502970 in complex with active-state GLP-1R revealed a unique binding pocket in the upper helical bundle where the compound is bound by the extracellular domain (ECD), extracellular loop 2, and transmembrane helices 1, 2, 3, and 7. This mechanism creates a distinct receptor conformation that may explain the partial agonism and biased signaling of the compound. Further, interaction between LY3502970 and the primate-specific Trp33 of the ECD informs species selective activity for the molecule. In efficacy studies, oral administration of LY3502970 resulted in glucose lowering in humanized GLP-1R transgenic mice and insulinotropic and hypophagic effects in nonhuman primates, demonstrating an effect size in both models comparable to injectable exenatide. Together, this work determined the molecular basis for the activity of an oral agent being developed for the treatment of type 2 diabetes mellitus, offering insights into the activation of class B GPCRs by nonpeptide ligands.

胰高血糖素样肽1受体（GLP-1R）激动剂是有效的抗糖尿病药物，可通过增强葡萄糖依赖性胰岛素分泌和改善能量平衡来发挥作用。目前批准的GLP-1R激动剂是基于肽的，事实证明很难获得具有最佳药物特性的小分子活化剂。我们报告了非肽GLP-1R激动剂LY3502970（OWL833）的发现和作用机理。LY3502970是部分激动剂，相对于GLP-1R处的β-arrestin募集，偏向G蛋白活化。该分子对其他BG类蛋白偶联受体（GPCR）具有很强的选择性，并且具有良好的药代动力学特性，适合口服。LY3502970与活动状态GLP-1R的复合物的高分辨率结构揭示了上螺旋束中的独特结合口袋，其中该化合物由细胞外域（ECD），细胞外环2和跨膜螺旋1、2结合参见图3和图7。该机制产生了独特的受体构象，其可以解释化合物的部分激动和偏向信号。此外，LY3502970与ECD的灵长类特异性Trp33之间的相互作用告知该分子具有物种选择性的活性。在功效研究中，口服LY3502970导致人源化GLP-1R转基因小鼠体内的葡萄糖降低，以及非人灵长类动物的促胰岛素和吞噬作用，这两种模型均显示了与可注射艾塞那肽相当的作用范围。一起，