Synthetic GPR40/FFAR1 agonists: An exhaustive survey on the most recent chemical classes and their structure-activity relationships

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.