Background: The global incidence of type 2 diabetes mellitus (T2DM) has enthused the development of new antidiabetic targets with low toxicity and long-term stability. In this respect, free fatty acid receptor 1 (FFAR1), which is also recognized as a G protein-coupled receptor 40 (GPR40), is a novel target for the treatment of T2DM. FFAR1/GPR40 has a high level of expression in β-cells of the pancreas, and the requirement of glucose for stimulating insulin release results in immense stimulation to utilise this target in the medication of T2DM.

Methods: The data used for this review is based on the search of several scienctific databases as well as various patent databases. The main search terms used were free fatty acid receptor 1, FFAR1, FFAR1 agonists, diabetes mellitus, G protein-coupled receptor 40 (GPR40), GPR40 agonists, GPR40 ligands, type 2 diabetes mellitus and T2DM.

Results: The present review article gives a brief overview of FFAR1, its role in T2DM, recent developments in small molecule FFAR1 (GPR40) agonists reported till now, compounds of natural/plant origin, recent patents published in the last few years, mechanism of FFAR1 activation by the agonists, and clinical status of the FFAR1/GPR40 agonists.

Conclusion: The agonists of FFAR1/GRP40 showed considerable potential for the therapeutic control of T2DM. Most of the small molecule FFAR1/GPR40 agonists developed were aryl alkanoic acid derivatives (such as phenylpropionic acids, phenylacetic acids, phenoxyacetic acids, and benzofuran acetic acid derivatives) and thiazolidinediones. Some natural/plant-derived compounds, including fatty acids, sesquiterpenes, phenolic compounds, anthocyanins, isoquinoline, and indole alkaloids, were also reported as potent FFAR1 agonists. The clinical investigations of the FFAR1 agonists demonstrated their probable role in the improvement of glucose control. Though, there are some problems still to be resolved in this field as some FFAR1 agonists terminated in the late phase of clinical studies due to “hepatotoxicity.” Currently, PBI-4050 is under clinical investigation by Prometic. Further investigation of pharmacophore scaffolds for FFAR1 full agonists as well as multitargeted modulators and corresponding clinical investigations will be anticipated, which can open up new directions in this area.

背景：全球2型糖尿病（T2DM）的发病率促使人们开发出毒性低，长期稳定的新型抗糖尿病药物。在这方面，游离脂肪酸受体1（FFAR1）也被认为是G蛋白偶联受体40（GPR40），是治疗T2DM的新靶标。FFAR1 / GPR40在胰腺的β细胞中具有高水平的表达，而刺激胰岛素释放的葡萄糖需求导致了巨大的刺激，需要在T2DM药物中利用该靶标。

方法：用于本综述的数据基于对几个科学数据库以及各种专利数据库的搜索。使用的主要检索词为游离脂肪酸受体1，FFAR1，FFAR1激动剂，糖尿病，G蛋白偶联受体40（GPR40），GPR40激动剂，GPR40配体，2型糖尿病和T2DM。

结果：本综述文章简要概述了FFAR1，其在T2DM中的作用，迄今为止报道的小分子FFAR1（GPR40）激动剂的最新进展，天然/植物来源的化合物，最近几年发表的最新专利，激动剂激活FFAR1，以及FFAR1 / GPR40激动剂的临床状态。

结论：FFAR1 / GRP40激动剂在T2DM的治疗控制中显示出相当大的潜力。所开发的大多数小分子FFAR1 / GPR40激动剂是芳基链烷酸衍生物（例如苯基丙酸，苯乙酸，苯氧乙酸和苯并呋喃乙酸衍生物）和噻唑烷二酮。FFAR1激动剂也被报道为某些天然/植物来源的化合物，包括脂肪酸，倍半萜烯，酚类化合物，花青素，异喹啉和吲哚生物碱。FFAR1激动剂的临床研究表明它们可能在改善血糖控制中发挥作用。但是，由于一些“ FFAR1激动剂”由于“肝毒性”而在临床研究后期终止，因此该领域仍有一些问题尚待解决。目前，PBI-4050正在接受Prometic的临床研究。有望进一步研究FFAR1全激动剂以及多靶点调节剂的药效团支架，并进行相应的临床研究，这将为这一领域开辟新的方向。