Discovery of Potent and Orally Bioavailable GPR40 Full Agonists Bearing Thiophen-2-ylpropanoic Acid Scaffold
Discovery of Potent and Orally Bioavailable GPR40 Full Agonists Bearing Thiophen-2-ylpropanoic Acid Scaffold
复制标题
发现具有噻吩-2-基丙酸支架的有效且口服生物可利用的 GPR40 完全激动剂
DOI：
10.1021/acs.jmedchem.6b01357
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发表时间：
2017-04-13
影响因子：
7.3
通讯作者：
Long, Ya-Qiu
中科院分区：
文献类型：
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作者：
Li, He;Huang, Qi;Long, Ya-Qiu
游离脂肪酸受体GPR 40主要在胰腺β细胞中表达，并以葡萄糖依赖性方式增强胰岛素分泌。因此，GPR 40激动剂可能是治疗2型糖尿病（T2 DM）的新型胰岛素促分泌素，低血糖风险降低或无低血糖风险。具有高安全性的化学和结构多样的GPR 40激动剂被用于基于GPR 40的药物治疗剂的临床开发。在这里，我们报告了我们的设计和发现的一种新的化学型的GPR 40激动剂的典型的苯丙酸支架。含有噻吩-2-基丙酸的GPR 40调节剂作为具有高效反应（E-max）和降低的亲脂性的完全激动剂发挥作用。值得注意的是，该系列中的先导化合物（R）-7k在体外葡萄糖刺激的胰岛素分泌和体内降糖作用（10 mg/kg，po）方面比曾经进入III期临床试验的GPR 40部分激动剂TAK-875更有效，并且对相关受体GPR 120和PPAR γ具有高选择性。
The free fatty acid receptor GPR40 is predominantly expressed in pancreatic beta-cells and enhances insulin secretion in a glucose dependent manner. Therefore, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia for the treatment of type 2 diabetes mellitus (T2DM). Chemically and structurally diverse GPR40 agonists with high safety are pursued for the clinical development of GPR40-based pharmacotherapeutics. Herein we report our design and discovery of a new chemotype of GPR40 agonists free of the typical phenylpropanoic acid scaffold. The thiophen-2-ylpropanoic acid containing GPR40 modulators functioned as full agonists with high-efficacy response (E-max) and reduced lipophilicity. Significantly, the lead compound in this series, (R)-7k, exhibited more potent in vitro glucose-stimulated insulin secretion and in vivo glucose-lowering effects (10 mg/kg, po) than the GPR40 partial agonist TAK-875, which was once in phase III clinical trials, and high selectivity over the relevant receptors GPR120 and PPAR gamma.