- Quinolone derivatives containing strained spirocycle as orally active glycogen synthase kinase 3β (GSK-3β) inhibitors for type 2 diabetics.
Quinolone derivatives containing strained spirocycle as orally active glycogen synthase kinase 3β (GSK-3β) inhibitors for type 2 diabetics.
Bioorganic & medicinal chemistry (2012-01-21)
Shigeki Seto, Kazuhiko Yumoto, Kyoko Okada, Yoshikazu Asahina, Aya Iwane, Maki Iwago, Reiko Terasawa, Kevin R Shreder, Koji Murakami, Yasushi Kohno
PMID22261023
ABSTRACT
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.
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