br Conclusion br Acknowledgements This work was

Conclusion
Acknowledgements This work was supported by a Grant-in-Aid for challenging Exploratory Research (15K12715) and was a partly supported by Suzuken Memorial Foundation (2014). The authors would like to thank Enago (www.enago.jp) for the English language review.
G protein-coupled receptor 120 (GPR120), also known as free fatty SKF 83566 hydrobromide sale receptor 4 (FFAR4), is a specific receptor for long-chain fatty acids (LCFA). It is highly expressed in intestine, macrophages and adipose tissue in both human and rodents., , , It was reported that the activation of GPR120 by long-chain fatty acids or small molecule agonists could promote the secretion of GLP-1 and thus increase glucose-stimulated insulin secretion. GPR120 agonism could also increase insulin sensitivity and display anti-diabetic effect by repressing chronic macrophage-induced tissue inflammation in obesity., , Therefore, GPR120 is emerging as a potential target for the treatment of obesity, type 2 diabetes and other chronic low-grade inflammatory diseases. The representative GPR120 agonists of are listed in . Availability of both potent and highly selective GPR120 agonists is quite challenging due to the fact that some GPR120 agonists are also GPR40 ligands, although the sequence homology between GPR120 and GPR40 is only 10%. (, ) is a dual GPR40/GPR120 agonist that is more favorable for GPR40 activation. (, ), obtained by modifying of a PPARγ ligand had only moderate potency for GPR120 activation and moderate selectivity for GPR120 over GPR40. (, ) with potent activity on GPR120 displayed a 1478 fold selectivity for GPR120 over GPR40. Compound was reported to be a nanomolar GPR120 agonist (EC = 35 nM) with high selectivity over GPR40. Compound was reported to have a moderate potency of GPR120 activation (EC = 0.2–2 μM), and this series compounds containing the (2,6-difluorophenoxy)carboxylic acid group showed good GPR120 activity. Together, discovery of novel GPR120 agonists with both high potency and high selectivity is highly desirable. In this study, we employed a hybrid design based on and () according to our speculation that the diflurobenzene moieties of and might be favorable for potent and selective activation of GPR120. Therefore, we designed and synthesized a series of biphenyl derivatives . Among them, compound exhibited potent GPR120 agonist activity (EC = 93 nM) and high selectivity over GPR40. Analysis of structure-activity relationship of was also performed. The general synthetic route to the biphenyl derivatives is shown in , , . (3-Methoxycyclobutoxy)benzene derivatives were prepared from commercially available anti-3-(benzyloxy) cyclobutan-1-ol and 3, 4-difluorophenol over four steps (reduction, Mitsunobu reaction, debenzylation and methylation). Borylation of gave boronates in the presence of iridium (I) catalyst. Phenols or thiophenes were reacted with bromoalkylcarboxylic acid methyl ester or ethyl ester in the presence of CsCO to give esters . Reaction of boronates with aryl bromides under Suzuki coupling condition afforded esters Esters were hydrolyzed to form carboxylic acids -, - and -. Ester (R = 2, 3-di-F, R = 3, 5-di-F, Y = S) was oxidized with mCPBA and followed by hydrolysis to afford carboxylic acid . Reaction of with methanesulfinamide or benzenesulfonamide in the presence of DMAP and EDCI in DCM gave -sulfonylamides or . Treatment of with thionyl chloride followed reaction with N-(2-hydroxyethyl) acetamide afforded ester (). In the similar pattern, carboxylic acids , and were prepared (). Ester reacted with boronate , then followed by hydrolysis to afford . Ester reacted with boronate under Suzuki coupling condition get phenol , phenol reacted with different alcohol under Mitsunobu reaction condition, then followed by hydrolysis to afford and . The GPR120 agonist activity of the compounds was evaluated by the calcium flux assay. The results are shown in . We found that compound exhibited good potent GPR120 agonist activity (EC = 93 nM) and high selectivity over GPR40 in this assay. To get GPR120 agonists with more GPR120 potency and high GPR120/GPR40 selectivity, the structure-activity relationship of compounds is summarized as below.