Acknowledgments Financial support from the

Acknowledgments Financial support from the National Natural Science Foundation of China (81730094, 81473262 and 81573299) is gratefully acknowledged. This project was also supported by the “111 Project” from the Ministry of Education of China, the State Administration of Foreign Expert Affairs of China (No. 111-2-07).
The prevalence of type 2 diabetes is increasing and has become a public health crisis in much of the world. The disorder is characterized by hyperglycemia, insulin-secreting β-cell dysfunction, and insulin resistance. Furthermore, many of the co-morbidities associated with diabetes, such as cardiovascular disease, kidney disease, neuropathy, and retinopathy, are mediated by inflammatory processes that are common in diabetics. GPR120 (Free Fatty Acid Receptor 4) is a 7-transmembrane GPCR that is activated by omega-3 fatty acids and is mainly expressed in the intestine, adipose, and macrophages. The activation of GPR120 has been implicated in a number of processes such as release of gastrointestinal peptides including glucagon-like peptide-1 (GLP-1), adipogenesis, lipogenesis, and tetracycline hydrochloride sale tolerance. Additionally, GPR120 is postulated to mediate anti-inflammatory and insulin-sensitizing effects in the adipose and macrophages. These benefits suggest that GPR120 agonists have the potential to be an effective treatment for type 2 diabetes. Thiophene and isothiazole were existing leads from our GPR120 agonist program (). While continuing investigations of those series, we were probing various substitutions of the central 5-membered heterocyclic ring to see if changing the heterocycle would give an increase in potency over and , or improved ADME or pharmacokinetic properties compared to the existing leads. In this vein, we decided to explore -arylpyrroles as GPR120 agonists. The initial SAR from the isothiazole series indicated that electron-withdrawing substituents on the pyrrole ring at the 3-position, in particular CF, were favored for GPR120 agonist activity. In addition, concerns about the instability of the electron-rich pyrrole ring compel the incorporation of electron-withdrawing groups as well. Synthesis of the 3-trifluoromethylpyrrole analogs starts with the bromination of phenylsulfonylpyrrole at the 3-position followed by installation of the 2-carbomethoxy to give ()., Treatment with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate in the presence of copper iodide gives an inseparable mixture of and . Reduction of the bromine of with hydrogen and Pd/C enables the isolation of from the undesired reduced product. Finally, deprotection of the phenylsulfonyl with TBAF gives the desired methyl 3-(trifluoromethyl)-1H-pyrrole-2-carboxylate Treatment with an arylboronic acid in the presence of copper acetate and pyridine gives the -arylpyrrole . Reduction of the ester with LAH followed by Mitsunobu reaction gives . Hydrolysis of the ester gives the desired acid , while reduction of the ester with LAH gives the alcohol . Because the trifluoromethylation step from the synthetic scheme above was not amenable to scale-up, an improved synthesis of intermediate was developed (). Condensation of 4-chloroaniline with ethyl 2-iodoacetate gives . Addition to 4-ethoxy-1,1,1-trifluorobut-3-en-2-one gives , which is cyclized with DBU in moderate yield to give the desired pyrrole . This new route enabled the multi-gram synthesis of lead compounds for studies. We first made a selection of compounds with substitution at the 3-position of the pyrrole to explore the SAR of this position (). At this early stage, we only made compounds with the 2,3-dimethyl- or 2,3-difluoro- substitution on the phenylpropionic acid moiety because these groups were known to afford good potency in other series. The unsubstituted pyrrole was active in the calcium mobilization assay, but discolored over time indicating air oxidation of this compound. Installing bromo and chloro at this position gave a similar level of potency, with the added benefit of air stability. The cyano group gave a large loss in potency while the CF group and gave a 2-fold boost in hGPR120 potency and was air stable. This established the CF as an optimal functional group at the 3-position of the pyrrole ring and was used in further analogs.