We undertook an optimization effort involving propan-2-yl 4-({6-[5-(methanesulfonyl)-2,3-dihydro-1H-indol-1-yl]pyrimidin-4-yl}oxy)piperidine-1-carboxylate 1, which we had previously discovered as a novel G protein-coupled receptor 119 (GPR119) agonist. To occupy a presumed hydrophobic space between the pyrimidine and piperidine rings in interaction with GPR119, we replaced the linker oxygen with nitrogen. Subsequently, the introduction of a substituent at the bridging nitrogen atom was explored. We found that the installation of N-trifluoromethyl group 10 not only enhanced GPR119 agonist activity but also considerably improved the human ether-à-go-go-related gene (hERG) inhibition profile. These improvements were not observed for non-fluorinated substituents, such as ethyl analog 8b. The next optimization effort focused on the exploration of a new surrogate structure for the indoline ring and the isosteric replacements of the piperidine N-Boc group to improve solubility, metabolic stability, and oral bioavailability. As a result, N-{1-[3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}-6-{[1-(methanesulfonyl)piperidin-4-yl]oxy}-N-(trifluoromethyl)pyrimidin-4-amine (27) was identified as a potent and orally bioavailable GPR119 agonist. This compound augmented insulin secretion and effectively lowered plasma glucose excursion in a diabetic animal model after oral administration. In this study, we discuss the designs, syntheses, and biological activities of a novel series of N-(piperidin-4-yl)-N-(trifluoromethyl)pyrimidin-4-amine derivatives as GPR119 agonists, and to determine the distinctive effect of the N-trifluoromethyl group on hERG inhibition, we also discuss the conformational preference of representative compounds.
Keywords: Aromatic ring count; Conformation; Fluorine; GPCR; GPR119 agonist; Metabolic stability; N-trifluoromethyl; Solubility; Type 2 diabetes mellitus; hERG.
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