The free fatty acid receptor 1 (FFAR1/GPR40) amplifies glucose‐dependent insulin secretion; therefore, it has attracted widespread attention as a promising antidiabetic target. Current clinical proof of concept also indicates that FFAR1 agonists achieve the initially therapeutic endpoint for the treatment of type 2 diabetes mellitus (T2DM) without the hypoglycemic risk. Thus, many pharmaceutical companies and academic institutes are competing to develop FFAR1 agonists. However, several candidates have been discontinued in clinical trials, often without reporting the underlying reasons. Herein, we review the challenges and corresponding strategies chosen by different medicinal chemistry teams to improve the physicochemical properties, potency, pharmacokinetics, and safety profiles of FFAR1 agonists, with a brief introduction to the biology and pharmacology of related targets.

中文翻译：

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游离脂肪酸受体1（FFAR1）作为2型糖尿病的新兴治疗靶标：最新进展和面临的挑战

游离脂肪酸受体1（FFAR1 / GPR40）放大葡萄糖依赖性胰岛素的分泌。因此，它作为有希望的抗糖尿病靶标受到了广泛的关注。当前的临床概念证明还表明，FFAR1激动剂可达到治疗2型糖尿病（T2DM）的初始治疗终点，且无低血糖风险。因此，许多制药公司和学术机构都在竞争开发FFAR1激动剂。但是，有几位候选人在临床试验中被中止，通常没有报告其根本原因。在此，我们回顾了不同药物化学小组选择的挑战和相应策略，以改善FFAR1激动剂的理化特性，效力，药代动力学和安全性，