Design,Synthesis, And Structure-Activity Relationship Of Novel G Protein-Coupled Receptor 40 Agonists Based On Phenylpropiolic Acid Scaffold

Type 2 diabetes (T2DM or non-insulin dependent diabetes mellitus) is a chronic disease caused by resistance to insulin action and defects in insulin secretion, which has impaired human health globally. G protein-coupled receptor 40 (GPR40 receptor or FFA1 receptor) is a G protein-coupled receptor (GPCR) which can be activated by medium to long chain fatty acids. It is considered to be a potential drug target and an important approach for the treatment of T2DM. The acivation of GPR40 has been shown to amplify free fatty acid-regulated glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells and leads to the improvement of glucose control.The structures of synthetic GPR40 agonists reported up to date are mostly based on the phenylpropionic acid function group or derivatives of phenylpropionic acid, while the structure of phenylpropiolic acid containing unsaturated bonds has not been studied as a function group of synthetic GPR40 agonists. For the study of this kind of novel agonists and its therapeutical effect we designed a series of compounds substituted by different residues on the base of the research achievement of the derivatives of phenylpropionic acid. Then we developed a series of reliable chemical synthesis methods, which are practical, stable and economic with acceptable yields of target compounds. By the screening of the agonist activities of these compounds we obtained some compounds with good performance. Compound 13 with two methyls at the 2-position and 6-position has the best activity among the synthesized compounds. At last we made a systematic SAR analysis, which could made a preparation and offer promising strategies for further improvement and optimization of this new type of GPR40 agonists.