GPR40/FFAR1 is a G-protein-coupled receptor expressed in pancreatic β-cells and enteroendocrine cells. GPR40 activation stimulates secretions of insulin and incretin, both of which are the pivotal regulators of glycemic control. Therefore, a GPR40 agonist is an attractive target for the treatment of type 2 diabetes mellitus. Using the reported biaryl derivative 1, we shifted the hydrophobic moiety to the terminal aryl ring and replaced the central aryl ring with piperidine, generating 2-(4,4-dimethylpentyl)phenyl piperidine 4a, which had improved potency for GPR40 and high lipophilicity. We replaced the hydrophobic moiety with N-alkyl-N-aryl benzamides to lower the lipophilicity and restrict the N-alkyl moieties to the presumed lipophilic pocket using the intramolecular π–π stacking of cis-preferential N-alkyl-N-aryl benzamide. Among these, orally available (3S)-3-cyclopropyl-3-(2-((1-(2-((2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid (SCO-267) effectively stimulated insulin secretion and GLP-1 release and ameliorated glucose tolerance in diabetic rats via GPR40 full agonism.

中文翻译：

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具有2-氨基甲酰基苯基哌啶部分的GPR40完全激动剂（SCO-267）的设计和鉴定。

GPR40 / FFAR1是在胰腺β细胞和肠内分泌细胞中表达的G蛋白偶联受体。GPR40激活刺激胰岛素和肠降血糖素的分泌，这两者都是血糖控制的关键调节剂。因此，GPR40激动剂是用于治疗2型糖尿病的有吸引力的靶标。使用所报道的联芳基衍生物1，我们将疏水部分移至末端芳基环，并用哌啶取代了中心芳基环，生成了2-（4,4-二甲基戊基）苯基哌啶4a，该化合物对GPR40的效力增强，亲脂性高。我们用N-烷基-N-芳基苯甲酰胺取代了疏水部分，以降低亲脂性并限制N使用顺式优先N-烷基-N-芳基苯甲酰胺的分子内π-π堆积将-烷基部分推定为亲脂性口袋。其中，可口服获得的（3 S）-3-环丙基-3-（2-（（1-（2-（（2,2-二甲基丙基）（6-甲基吡啶-2-基氨基甲酰基）-5-甲氧基苯基））哌啶-4-基）甲氧基）吡啶-4-基）丙酸（SCO-267）通过GPR40完全激动有效地刺激了糖尿病大鼠的胰岛素分泌和GLP-1释放并改善了糖耐量。