Discovery of Potent and Orally Bioavailable GPR40 Full Agonists Bearing Thiophen-2-ylpropanoic Acid Scaffold,Journal of Medicinal Chemistry

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Discovery of Potent and Orally Bioavailable GPR40 Full Agonists Bearing Thiophen-2-ylpropanoic Acid Scaffold
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-03-17 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01357
He Li _{1,

2} , Qi Huang _{1,

2} , Cheng Chen _{1,

3} , Bin Xu ₃ , He-Yao Wang ₁ , Ya-Qiu Long ₁

Affiliation

The free fatty acid receptor GPR40 is predominantly expressed in pancreatic β-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 PPARγ.

中文翻译：

发现带有噻吩-2-基丙酸支架的强效和口服生物可用的GPR40激动剂

游离脂肪酸受体GPR40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，GPR40激动剂可能是治疗2型糖尿病（T2DM）的低血糖风险降低或没有低血糖风险的新型胰岛素促分泌剂。化学和结构多样的GPR40激动剂具有很高的安全性，可用于基于GPR40的药物治疗药物的临床开发。在此，我们报告了我们的设计和发现的一种新型GPR40激动剂的化学型，该激动剂不含典型的苯丙酸支架。含有GPR40调节剂的噻吩-2-基丙酸起完全激动剂的作用，具有高效率响应（E _max）和降低的亲脂性。重要的是，该系列中的先导化合物（R）-7k，比GPR40部分激动剂TAK-875表现出更强的体外葡萄糖刺激的胰岛素分泌和降低体内葡萄糖的作用（10 mg / kg，口服），且该选择性曾在III期临床试验中，并且选择性高超过相关受体GPR120和PPARγ。

更新日期：2017-03-17

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