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 a...

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Veröffentlicht in:	Bioorganic & medicinal chemistry 2012-02, Vol.20 (3), p.1188-1200
Hauptverfasser:	Seto, Shigeki, Yumoto, Kazuhiko, Okada, Kyoko, Asahina, Yoshikazu, Iwane, Aya, Iwago, Maki, Terasawa, Reiko, Shreder, Kevin R., Murakami, Koji, Kohno, Yasushi
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Biological and medical sciences blood glucose chemistry Diabetes Mellitus, Type 2 - drug therapy Diabetes Mellitus, Type 2 - enzymology Drug Design Glucose Tolerance Test glucose tolerance tests Glycogen Synthase Kinase 3 - antagonists & inhibitors Glycogen Synthase Kinase 3 - metabolism Glycogen Synthase Kinase 3 beta glycogen synthase kinases GSK-3β inhibitor Hep G2 Cells Humans inhibitory concentration 50 Male Medical sciences Mice Models, Molecular noninsulin-dependent diabetes mellitus Pharmacology. Drug treatments quinolones Quinolones - chemical synthesis Quinolones - chemistry Quinolones - pharmacokinetics Quinolones - pharmacology Spiro Compounds - chemical synthesis Spiro Compounds - chemistry Spiro Compounds - pharmacokinetics Spiro Compounds - pharmacology Spirocycle Tricyclic quinolones
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Beschreibung
Zusammenfassung:	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 (IC50 = 36nM, EC50 = 3.2μM, respectively). Additionally, 44 decreased the plasma glucose concentration dose-dependently after an oral glucose tolerance test in mice.
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2011.12.046