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.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Diabetes Mellitus, Type 2 / drug therapy*
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Diabetes Mellitus, Type 2 / enzymology
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Drug Design
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Glucose Tolerance Test
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Glycogen Synthase Kinase 3 / antagonists & inhibitors*
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Hep G2 Cells
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Humans
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Male
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Mice
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Models, Molecular
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Quinolones / chemical synthesis
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Quinolones / chemistry*
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Quinolones / pharmacokinetics
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Quinolones / pharmacology*
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Spiro Compounds / chemical synthesis
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Spiro Compounds / chemistry
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Spiro Compounds / pharmacokinetics
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Spiro Compounds / pharmacology
Substances
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Quinolones
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Spiro Compounds
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Glycogen Synthase Kinase 3