School of Pharmaceutical Science, Jiangnan University, Wuxi, Jiangsu, China.
Jiangyin Tianjiang Pharmaceutical Co. Ltd, Wuxi, Jiangsu, China.
Chem Biol Drug Des. 2019 May;93(5):900-909. doi: 10.1111/cbdd.13480. Epub 2019 Jan 29.
Free fatty acid 1 (FFA1/GPR40) has attracted extensive attention as a novel target for the treatment of type 2 diabetes for its role in the enhancement of insulin secretion with glucose dependency. Aiming to develop novel potent FFA1 agonists, a new series of phenylpropionic acid derivatives were designed and synthesized on the basis of the modification of chemical cement of TAK-875, AMG-837, and LY2881835. Among them, most promising compounds 7, 14, and 15 were obtained with EC values of 82, 79, and 88 nM, exhibiting a powerful agonistic activity compared to TAK-875 (95.1 nM). During Oral glucose tolerance test in normal mice, compound 7, 14, and 15 had significant glucose-lowering effect at the dose of 50 mg/kg. Furthermore, compound 15 (50 mg/kg) also significantly improved in glucose tolerance in type 2 diabetic mice. Herein, we reported the discovery and optimization of a series of potent FFA1 agonists. The discovery supported further exploration surrounding this scaffold.
游离脂肪酸 1（FFA1/GPR40）作为治疗 2 型糖尿病的新型靶点，因其在葡萄糖依赖性增强胰岛素分泌方面的作用而受到广泛关注。为了开发新型有效的 FFA1 激动剂，我们在 TAK-875、AMG-837 和 LY2881835 的化学结构修饰的基础上，设计并合成了一系列苯丙酸衍生物。其中，化合物 7、14 和 15 最有前途，EC 值分别为 82、79 和 88 nM，与 TAK-875（95.1 nM）相比具有强大的激动活性。在正常小鼠的口服葡萄糖耐量试验中，化合物 7、14 和 15 在 50 mg/kg 剂量下具有显著的降血糖作用。此外，化合物 15（50 mg/kg）在 2 型糖尿病小鼠中也显著改善了葡萄糖耐量。本研究报道了一系列强效 FFA1 激动剂的发现和优化。这一发现为进一步探索该骨架提供了支持。
