Discovery of AM-6226: A Potent and Orally Bioavailable GPR40 Full Agonist That Displays Efficacy in Nonhuman Primates,ACS Medicinal Chemistry Letters

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Discovery of AM-6226: A Potent and Orally Bioavailable GPR40 Full Agonist That Displays Efficacy in Nonhuman Primates
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-06-06 00:00:00 , DOI: 10.1021/acsmedchemlett.8b00213
Sean P. Brown ₁ , Paul Dransfield ₁ , Marc Vimolratana ₁ , Liusheng Zhu ₁ , Jian Luo ₁ , Jane Zhang ₁ , XianYun Jiao ₁ , Vatee Pattaropong ₁ , Simon Wong ₁ , Run Zhuang ₁ , Gayathri Swaminath ₁ , Jonathan B. Houze ₁ , Daniel C.-H. Lin ₁

Affiliation

GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets and enteroendocrine L-cells, and, when activated, elicits increased insulin secretion only in the presence of elevated glucose levels. We recently reported the discovery of AM-1638 (2), a full agonist of GPR40. Herein, we present further structure–activity relationships progressing from AM-1638 (2) to AM-6226 (14) that possesses a profile acceptable for dosing cynomolgus monkeys. The GPR40 full agonist AM-6226 (14) is the first molecule to display significant glucose lowering in cynomolgus monkeys providing additional evidence that GPR40 full agonists afford access to a powerful mechanism for maintaining glycemic control.

中文翻译：

AM-6226的发现：一种有效的口服生物可利用的GPR40完全激动剂，可在非人类灵长类动物中显示功效

GPR40（FFA1）是一种G蛋白偶联受体，主要在胰岛和肠内分泌L细胞中表达，并在激活后仅在葡萄糖水平升高时引起胰岛素分泌增加。我们最近报道了GPR40的完全激动剂AM-1638（2）的发现。在这里，我们提出了从AM-1638（2）到AM-6226（14）的结构-活性关系，该关系具有食蟹猕猴可接受的特性。GPR40完全激动剂AM-6226（14）是第一个在食蟹猴中表现出显着葡萄糖降低的分子，提供了其他证据表明GPR40完全激动剂提供了维持血糖控制的有效机制。

更新日期：2018-06-06

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