Lead generation and optimization of novel GPR119 agonists with a spirocyclic cyclohexane structure.

We describe here the generation of a lead compound and its optimization studies that led to the identification of a novel GPR119 agonist. Based on a spirocyclic cyclohexane structure reported in our previous work, we identified compound 8 as a lead compound, being guided by ligand-lipophilicity efficiency (LLE), which linked potency and lipophilicity. Subsequent optimization studies of 8 for improvement of solubility afforded representative 21. Compound 21 had no inhibitory activity against six CYP isoforms and showed favorable pharmacokinetic properties and hypoglycemic activity in rats.

Optimization of oxadiazole derivatives with a spirocyclic cyclohexane structure as novel GPR119 agonists.

We describe here a novel GPR119 agonist 24, which showed a potent and long-acting hypoglycemic effect in rats via oral dosing. For the discovery of 24, we chose compound 5, which possessed an oxadiazole linker, as a lead compound among our spirocyclic cyclohexane GPR119 agonist series, taking into account its lower plasma protein binding nature. 3,5-Difluoro and 4-methylsulfonylmethy groups on the left side phenyl group, and a gem-difluoro group on the right side of 24 are important for its agonist potency and metabolic stability, respectively.

Design and synthesis of novel and potent GPR119 agonists with a spirocyclic structure.

Exploration of alternative structures of the substituted piperidine or piperazine ring which are characteristic in most of the reported GPR119 agonists provided novel spirocyclic cyclohexane derivatives. The representative 17 with a high three-dimensionality exhibited potent agonistic activity (EC50 = 4 nM) with no CYP inhibitory activity (IC50 >10 µM). Compound 17 also displayed hypoglycemic activity with insulin secretion dependent on glucose concentration in an intraperitoneal glucose tolerance test in rats.

Rhodium-catalyzed methylthio transfer reaction between ketone alpha-positions: reversible single-bond metathesis of C-S and C-H bonds.

In the presence of a catalytic amount of RhH(PPh(3))(4) and 1,2-bis(diphenylposphino)ethane (dppe), alpha-phenylthio ketones were methylthiolated with p-cyano-alpha-methylthioacetophenone giving alpha-phenylthio-alpha-methylthio ketones. The methylthio transfer reaction between the ketone alpha-positions was reversible and at equilibrium, and the methylthio group was transferred in preference to the phenylthio group. The reaction of tertiary alkyl methylthiomethyl ketones proceeded in high yields; the reaction of diastereomeric 4-(tert-butyl)-2-phenylthiocyclohexanones gave an axial 2-methylthiolated product.

One-step synthesis of triethynylvinylmethanes and tetraethynylmethanes by GaCl(3)-promoted diethynylation of 1,4-enynes and 1,4-diynes.

The treatment of 1,4-enynes with chlorotriethylsilylacetylene at 130 degrees C in the presence of GaCl3 gave triethynylvinylmethanes by the diethynylation at the allylic methylene moiety. The addition of 2,6-di(tert-butyl)-4-methylpyridine and tert-butyldiphenylsilanol considerably improved the yields of the products by reducing the decompositions of the substrates and products. The reaction should involve the initial formation of allylgallium from the enynes and GaCl3, where GaCl3 activated hydrocarbon C-H to generate a nucleophilic organogallium intermediate. Carbometalation with chloroacetylene followed by beta-elimination then led to the ethynylated product. Triethynylvinylmethanes were obtained by the repeated regioselective ethynylation at the 3-position of the enynes. The reaction of allylsilanes with the chloroacetylene also gave diethynylvinylmethanes, in which 1,4-enynes were formed in situ by the addition-elimination of allylgallium formed from allylsilane and GaCl3. Tetraethynylmethanes were obtained by reacting 1,4-diynes with the chloroacetylene at 150 degrees C. The structure and amount of silanol can be used to control the reactivity of GaCl3.