After the synthesis of methylsulfonyl or

After the synthesis of methylsulfonyl or tetrazole surrogate derivatives, compounds synthesized by introducing hydrogen, fluoro, and methyl groups into the head group of GPR119 agonists were synthesized. Compounds – were synthesized by reacting hydroxybenzaldehyde with fluorine, hydrogen, or a methyl group with compound . Compounds – were synthesized by reacting with 3-(triphenylphosphoranylidene) succinimide. Compounds –, obtained by removing the Boc protection group via treatment with HCl, were reacted with 2-chloro-5-ethylpyrimidine to synthesize compounds , , and . Compounds – were reacted with isobutylene oxide to synthesize compounds –. Compounds – were obtained by treating the hydroxyl group with a fluorine group using Deoxo-Fluor®. Introduction of 2,4-thiazolidinedione as the polar head resulted in compound , which had weak GPR119 agonistic potency (% activation relative to GSK1292263 (100%) at 1 μM) and an EC = 780 nM (). Compounds containing polar head moieties with rhodanine (, 3-aminorhodanine (, or carboxylic Tubastatin A ( had no agonistic effects. Compound containing a 3-phenyl pyrrolidin-2,5-dione polar head group, had a potency comparable to that of MBX-2982. Pyrrolidine-2,5-dione can act as a strong hydrogen bond acceptor and replace the surrogate of the tetrazole group of MBX-2982. To demonstrate this, we removed the bulky phenyl group from 3-phenyl pyrrolidin-2,5-dione and found that the activity of compound increased to EC = 49 nM. Pyrrolidin-2-one is a CO group-absent form present in pyrrolidine-2,5-dione. Compared with compound , the agonistic effect of compound was 2-fold increased. However, when phenyl, morpholine, tetrahydropyran, or aminoalkyl chains were attached to the nitrogen position of the pyrrolidine-2,5-dione, potency was decreased compared to that of compound . We determined that pyrrolidine-2,5-dione was the most appropriate functional group from the activity data shown in . Therefore, other compounds needed to be modified by fixing the polar head with pyrrolidine-2,5-dione. As shown by the agonistic effect of compounds –, of which phenyl ring was substituted with hydrogen, methyl, and difluoride groups instead of a fluorine atom, compounds and , with fluorophenyl and tolyl, had good activity, but the activity of compounds and with phenyl and difluorophenyl, was not good. In particular, the activity of compound was superior to that of compound . Compounds , , and were prepared by substituting carbamate -butyl groups with ethyl pyrimidine groups to improve metabolic stability. Overall, activity was good and compound (EC = 18 nM) with tolyl was more active than compound (EC = 49 nM) with a fluorophenyl ring. Compounds – and – were obtained by replacing ethylpyrimidine with -alcohol and fluorine, respectively, in the tail moiety, but no agonistic effect was observed. The data shown in , , indicated that and should be selected as prototype compounds. Compounds and were evaluated for stability, ability to induce or inhibit CYP, hERG binding, and cytotoxicity. As shown in , compounds and were more metabolically stable than MBX-2982 in human and rat liver microsomes. In CYP inhibition assays with several CYP subtypes, compounds and did not significantly inhibit CYP and showed no hERG binding. To evaluate efficacy, an oral glucose tolerance test (OGTT) was performed with compounds and . Plasma glucose levels were determined based on the AUC of the glucose concentration and were reduced at the 30 mg/kg dose. The efficacy of these two compounds was similar to that of MBX-2982 (). In conclusion, we identified a series of thiazole derivatives as GPR119 agonists containing pyrrolidine-2,5-dione. These compounds had a polar head as a novel methanesulfonyl/tetrazole surrogate in structures of GPR119 agonists. The substitution of pyrrolidine-2,5-dione for the tetrazole ring of MBX-2982 compound as a novel polar head moiety resulted in increased activity for GPR119 and improved pharmacokinetic profiles. Several compounds showed good agonistic activity (EC < 100 nM) and potency. Among them, compounds and showed good activities with EC values of 49 nM and 18 nM, respectively. These compounds did not exhibit significant CYP inhibition, hERG binding, or cytotoxicity.