Orally bioavailable, synthetic nonpeptide agonists (NPAs) of the glucagon-like peptide-1 receptor (GLP-1R) may offer an effective, scalable pharmacotherapy to address the metabolic disease epidemic. One of the first molecules in the emerging class of GLP-1R NPAs is orforglipron, which is in clinical development for treating type 2 diabetes and obesity. Here, we characterized the pharmacological properties of orforglipron in comparison with peptide-based GLP-1R agonists and other NPAs. Competition binding experiments using either [ 125 I]GLP-1(7-36)NH 2 or [ 3 H]orforglipron indicated that orforglipron is a high-affinity [inhibition constant ( K i ) = 1 nM], selective ligand of the human GLP-1R. Signal transduction assays showed that orforglipron has low intrinsic efficacy for effector activation and negligible β-arrestin recruitment. To evaluate GLP-1R engagement in vivo, mice expressing the human GLP-1R were administered orforglipron and subjected to a glucose tolerance test. Predicted receptor occupancy was calculated using the receptor K i value of orforglipron and its unbound concentration in vivo that reduces hyperglycemia. These experiments revealed that low GLP-1R occupancy by orforglipron is sufficient to yield a full biological response. Moreover, in a model where CRISPR-Cas9 gene editing was used to sensitize the rat GLP-1R ( Glp1r S33W ) to GLP-1R NPAs, target engagement by orforglipron in the pancreas and brain was consistent with peptide-based GLP-1R agonists. Diet-induced obesity in Glp1r S33W rats enabled studies showing weight loss in animals orally administered orforglipron versus subcutaneous injection of GLP-1R agonist semaglutide. Furthermore, crossover studies indicated oral orforglipron can sustain efficacy initiated by parenteral semaglutide. The pharmacological properties of orforglipron may inform targeting of other peptide receptors with NPAs.

中文翻译：

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orforglipron 对 GLP-1 受体非肽激动作用的药理学基础


胰高血糖素样肽-1 受体 （GLP-1R） 的口服生物可利用的合成非肽激动剂 （NPA） 可能提供一种有效、可扩展的药物治疗来解决代谢性疾病的流行。新兴的 GLP-1R NPA 类别中的首批分子之一是 orforglipron，它正在临床开发中，用于治疗 2 型糖尿病和肥胖症。在这里，我们表征了 orforglipron 与基于肽的 GLP-1R 激动剂和其他 NPA 相比的药理学特性。使用 [ 125 I]GLP-1（7-36）NH 2 或 [ 3 H] orforglipron 的竞争结合实验表明，orforglipron 是人 GLP-1R 的高亲和力 [抑制常数 （Ki） = 1 nM] 选择性配体。信号转导测定显示，orforglipron 对效应子激活的内在功效较低，β-arrestin 募集可忽略不计。为了评估 GLP-1R 在体内的参与，给予表达人 GLP-1R 的小鼠 orforglipron 并进行葡萄糖耐量试验。使用 orforglipron 的受体 Ki 值及其体内降低高血糖的未结合浓度计算预测的受体占有率。这些实验表明，orforglipron 的低 GLP-1R 占有率足以产生完整的生物反应。此外，在使用 CRISPR-Cas9 基因编辑使大鼠 GLP-1R （ Glp1r S33W ） 对 GLP-1R NPA 敏感的模型中，奥格列隆在胰腺和大脑中的靶标参与与基于肽的 GLP-1R 激动剂一致。饮食诱导的 Glp1r S33W 大鼠肥胖使研究表明，与皮下注射 GLP-1R 激动剂 semaglutide 相比，口服 orforglipron 的动物体重减轻。此外，交叉研究表明，口服奥格列吡隆可以维持肠外索马鲁肽引发的疗效。 orforglipron 的药理学特性可能为 NPA 靶向其他肽受体提供信息。