Discovery of 3-(4-methanesulfonylphenoxy)-N-[1-(2-methoxy-ethoxymethyl)-1H-pyrazol-3-yl]-5-(3-methylpyridin-2-yl)-benzamide as a novel glucokinase activator (GKA) for the treatment of type 2 diabetes mellitus

Compound 19e, a Novel Glucokinase Activator, Protects against Cytokine-Induced Beta-Cell Apoptosis in INS-1 Cells

“…To elucidate this pathway, we first examined whether synthesized GKA compounds (compound 19 and compound 19e) ( Figure 2A ), previously identified as potent GKAs (Park et al, 2014, 2015), exert toxicity on INS-1 cells. After 24 h of treatment, cytotoxicity was not observed at any concentration (2.5 ∼ 40 μM), and an increased cell viability was demonstrated with concentrations of 5, 10, and 20 μM of the compounds ( Figure 2B ).…”

“…Therefore, the preventive effect of compound 19e against the deleterious effects of proinflammatory cytokines would be beneficial to preserve functional beta-cell mass. Moreover, compound 19e treatment increased the number of beta-cells via upregulation of IRS-2 expression (data not shown), suggesting that a proliferative effect as well as an anti-apoptotic effect might be mechanisms by which compound 19e induced significant reduction in blood glucose levels in db/db mice (Park et al, 2014). …”

“…A number of allosteric small-molecule GKAs have been developed, and their efficacy has been investigated on beta-cells and in diabetic mice. Previously, compound 19e was discovered as a novel glucokinase, demonstrating hypoglycemic effects in diabetic db / db mice (Park et al, 2014). In this study, the anti-apoptotic effects and mechanisms of compound 19e were investigated in INS-1 beta-cells treated with cytokines to induce cell death.…”

“…The novel GKAs, compound 19 and 19e, were prepared by Yuhan Research Institute (Yongin-si, South Korea) (Park et al, 2014) and were dissolved in dimethylsulfoxide. (2R)-2-(4-cyclopropanesulphonylphenyl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl) propionamide (PSN-GK1), a GKA (Fyfe et al, 2007), and exendin-4 (Sigma-Aldrich, St. Louis, MO, USA), a GLP-1 receptor agonist, were used as positive controls.…”

“…Both compounds show glucose-lowering activities in C57BL/6J and db/db mice with no evidence for hypoglycemia risk (Park et al, 2014, 2015). The effect of these GKA compounds on beta-cell apoptosis was evaluated, and as only compound 19e showed anti-apoptotic effects against cytokine-induced beta-cell death, we investigated the mechanisms involved.…”