Kyoko Okada

Quinolone derivatives containing strained spirocycle as orally active glycogen synthase kinase 3β (GSK-3β) inhibitors for type 2 diabetics.

The design, synthesis, and evaluation of 6-6-7 tricyclic quinolones containing the strained spirocycle moiety aiming at the GSK-3β inhibitor were described. Among the synthesized compounds, 44, having a cyclobutane ring on a spirocycle, showed excellent GSK-3β inhibitory activity in both cell-free and cell-based assays (IC(50) = 36nM, EC(50) = 3.2μM, respectively). Additionally, 44 decreased the plasma glucose concentration dose-dependently after an oral glucose tolerance test in mice.

Design, Synthesis, and Structure−Activity Relationship Studies of Novel 2,4,6-Trisubstituted-5-pyrimidinecarboxylic Acids as Peroxisome Proliferator-Activated Receptor γ (PPARγ) Partial Agonists with Comparable Antidiabetic Efficacy to Rosiglitazone

A series of novel 2,4,6-trisubstitutedpyrimidine-5-carboxylic acid derivatives were designed and synthesized with the intent of producing a peroxisome proliferator-activated receptor gamma (PPARgamma) partial agonist for antidiabetic agents. A pharmacophore-driven approach of in-house screening identified compound 7, which led to the identification of compound 9 featuring a 2,4,6-trisubstituted pyrimidine-5-carboxylic acid core. Structure-activity relationship studies of 9 resulted in identifying 4,6-bisbenzylthio-2-methylthiopyrimidine-5-carboxylic acid (50) as the most attractive of all the screened compounds. The X-ray cocrystal structure of 50 bound on PPARgamma revealed that the key hydrogen bond interactions, which are not related to the activation function 2 (AF-2) site, are different from those of the full agonist. Compound 50 showed typical PPARgamma partial agonist properties in the PPARgamma-GAL4 functional assay and weaker differentiation of adipocytes in 3T3-L1 cells than observed with rosiglitazone. Furthermore, 50 displayed comparable antidiabetic efficacy with rosiglitazone in db/db mice, although its potency is 10-fold weaker than that of rosiglitazone.

Synthesis and structure-activity relationship of 4-quinolone-3-carboxylic acid based inhibitors of glycogen synthase kinase-3β.

The synthesis, GSK-3β inhibitory activity, and anti-microbial activity of bicyclic and tricyclic derivatives of the 5,7-diamino-6-fluoro-4-quinolone-3-carboxylic acid scaffold were studied. Kinase selectivity profiling indicated that members of this class were potent and highly selective GSK-3 inhibitors.

6-Position optimization of tricyclic 4-quinolone-based inhibitors of glycogen synthase kinase-3β: discovery of nitrile derivatives with picomolar potency.

We previously disclosed tricylic, 6-carboxylic acid-bearing 4-quinolones as GSK-3β inhibitors. Herein we discuss the optimization of this series to yield a series of more potent 6-nitrile analogs with insignificant anti-microbial activity. Finally, kinase profiling indicated that members of this class were highly specific GSK-3 inhibitors.