Free fatty acid receptor 1 (FFAR1 or GPR40) is a potential target for treating type 2 diabetes mellitus (T2DM) and related disorders that have been extensively researched for many years. GPR40/FFAR1 is a promising anti-diabetic target because it can activate insulin, promoting glucose metabolism. It controls T2DM by regulating glucose levels in the body through two separate mechanisms: glucose-stimulated insulin secretion and incretin production. In the last few years, various synthetic GPR40/FFAR1 agonists have been discovered that fall under several chemical classes, viz. phenylpropionic acid, phenoxyacetic acid, and dihydrobenzofuran acetic acid. However, only a few synthetic agonists have entered clinical trials due to various shortcomings like poor efficacy, low lipophilicity and toxicity issues. As a result, pharmaceutical firms and research institutions are interested in developing synthetic GPR40/FFAR1 agonists with superior effectiveness, lipophilicity, and safety profiles. This review encompasses the most recent research on synthetic GPR40/FFAR1 agonists, including their chemical classes, design strategies and structure-activity relationships. Additionally, we have emphasised the structural characteristics of the most potent GPR40/FFAR1 agonists from each chemical class of synthetic derivatives and analysed their chemico-biological interactions. This work will hopefully pave the way for developing more potent and selective synthetic GPR40/FFAR1 agonists for treating T2DM and related disorders.

游离脂肪酸受体 1（FFAR1 或 GPR40）是治疗 2 型糖尿病 (T2DM) 及相关疾病的潜在靶点，已被广泛研究多年。 GPR40/FFAR1 是一个有前途的抗糖尿病靶点，因为它可以激活胰岛素，促进葡萄糖代谢。它通过两种不同的机制调节体内的葡萄糖水平来控制 T2DM：葡萄糖刺激的胰岛素分泌和肠促胰岛素的产生。在过去的几年中，已经发现了各种合成的 GPR40/FFAR1 激动剂，它们属于多种化学类别，即。苯丙酸、苯氧基乙酸和二氢苯并呋喃乙酸。然而，由于疗效差、亲脂性低和毒性等问题，只有少数合成激动剂进入临床试验。因此，制药公司和研究机构有兴趣开发具有卓越有效性、亲脂性和安全性的合成 GPR40/FFAR1 激动剂。本综述涵盖了合成 GPR40/FFAR1 激动剂的最新研究，包括其化学类别、设计策略和构效关系。此外，我们还强调了每个化学类别的合成衍生物中最有效的 GPR40/FFAR1 激动剂的结构特征，并分析了它们的化学生物相互作用。这项工作有望为开发更有效和选择性的合成 GPR40/FFAR1 激动剂来治疗 T2DM 和相关疾病铺平道路。