GPR is a member of the G protein
GPR119 is a member of the G protein-coupled receptor family, and is highly expressed in pancreatic β-cells and intestinal endocrine cells. It has been proposed that GPR119 agonists modulate glucose homeostasis by indirectly stimulating glucose-dependent insulin release through enhancing pancreatic cell function and releasing incretin hormones from the small intestine. Coupled with the ability to enhance insulin secretion only when glucose levels are elevated, its selective expression makes GPR119 a very attractive target for the development of new drugs for T2DM. Recently, a large number of synthetic low-molecular weight GPR119 agonists have been synthesized and compounds, such as MBX-2982, GSK1292263, APD668, APD597, and BMS-903452, have entered clinical trials. A general structure of the GPR119 agonist, consisting of the head, linker, and tail moieties, was proposed. The head portion had an aromatic ring containing an electron withdrawing group (EWG), such as a sulfonyl group or a fluorine atom. The tail moiety had a piperidine group with a bulky carbamate or its bioisostere (). In our efforts to discover pharmacologically superior GPR119 agonists, thiazole compound MBX-2982 was selected as a lead structure and planned to replace the head, linker and tail moieties to the diverse functional groups (, , ). With this purpose, we introduce the synthesis and biological evaluation of a series of thiazole derivatives containing pyrrolidine-2,5-dione as the EWG and the optimization of the head and tail moieties as potential GPR119 agonists for the treatment of T2DM. The general synthetic procedures are outlined in , , . GPR119 agonist activity was evaluated by replacing the ethyl group present in the pyrimidine ring of the tail moiety of the MBX-2982 compound, which was developed as a GPR119 agonist, with various functional groups. Commercially available 5-bromo-2-chloropyrimidine was coupled with ethyl acrylate by Heck reaction in the presence of Pd(OAc) catalyst to yield , which was reduced using Pd/C under a hydrogen Costunolide to obtain compound . -Boc-piperidine-4-carboxamide (compound was converted to -Boc-piperidine-4-carbothioamide (compound using Lawesson's reagent after protecting the nitrogen atom present in 4-piperidinecarboxamide with Boc anhydride. Compound was synthesized by reacting compound with 1,3-dichloroacetone to form a thiazole ring. Compound was obtained by reacting compound with 4-(1-tetrazol-1-yl) phenol in the presence of base. The Boc protecting group of compound was removed using HCl to obtain compound . This compound was reacted with compound to synthesize compound , which obtained an acid functional group through hydrolysis. Compound was coupled with various amines using HBTU to produce amide –. Compound , which had an azide group in the ethylene glycol moiety, synthesized compound with had an amine through Pd/C and H reduction. We synthesized compound by reacting a portion of MBX-2982 with a biguanide group, the main component of the drug, metformin, which is currently used for treating T2DM. shows the activity evaluation results of MBX-2982 and the tail moiety modified thiazole derivatives. As shown, MBX-2982 showed 91% activation at 1 μM compared to GSK1292263, which was used as a reference molecule in the efficacy evaluation. In addition, the EC value for human GPR119 is 87 nM. Compound was a novel compound synthesized by combining part of MBX-2982 with part of a biguanide, but it did not activate GPR119. Compound (with an acid functional group), compound (with a trimethylammonium chloride salt), and compound (with an ethylamine moiety) did not show any activity. Thereafter, we conducted an experiment to convert the tail moiety to an ethylpyrimidine group and modify the head moiety. GPR119 agonists have a strong hydrogen bond acceptor, such as a methyl sulfonyl or tetrazole group, in the head moiety. We synthesized compounds containing methylsulfonyl or tetrazole surrogates as novel hydrogen bonding acceptors in GPR119 agonists (). To identify novel sulfone or tetrazole surrogates, various functional groups, including 2,4-thiazolidinedione, rhodanine, 3-aminorhodanine, carboxylic acid, pyrrolidin-2-one, and pyrrolidine-2,5-dione, were introduced on the aromatic ring. Compound was reacted with 3-fluoro-4-hydroxyphenol to afford compound The Boc group was removed by treatment with HCl and reaction with 2-chloro-5-ethylpyrimidine to afford compound . Compound and various kinds of heterocyclic compounds were reacted using the Knoevenagel condensation reaction to obtain compounds –. To obtain compound , 3-(triphenylphosphoranylidene) succinimide was synthesized by reacting maleimide with triphenylphosphine, then compound . Compound was obtained by reacting 1-acetylpyrrolidin-2-one with -BuOK and compound . Compound – having morpholine, tetrahydropyran or aminoalkyl chain as a head moiety were synthesized using alkylation with compound .