Abstract
In an effort to develop new molecules with improved antihyperlipidemic activity, eight new 2-azetidinone analogs (4a-4h) of ezetimibe were designed through in silico docking experiments with the crystal structure of the Niemann-Pick C1-like 1 protein (NPC1L1). Synthesis and further antihyperlipdemic evaluation of this series in the Triton WR 1339 induced hyperlipidemic rat model showed some of the molecules to exhibit significant lipid-lowering effects comparable to ezetimibe. Correlation between the observed biological activity and the in silico molecular docking scores of the compounds was observed.
Keywords:
2-Azetidinone; Antihyperlipidemic; Ezetimibe; Molecular docking; NPC1L1.
© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
MeSH terms
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Animals
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Azetidines / chemical synthesis*
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Azetidines / metabolism
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Azetidines / pharmacology*
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Binding Sites
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Biomarkers / blood
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Crystallography, X-Ray
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Disease Models, Animal
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Drug Design*
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Ezetimibe
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Female
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Hyperlipidemias / blood
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Hyperlipidemias / chemically induced
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Hyperlipidemias / drug therapy*
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Hypolipidemic Agents / chemical synthesis*
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Hypolipidemic Agents / metabolism
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Hypolipidemic Agents / pharmacology*
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Lipids / blood
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Male
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Membrane Proteins / chemistry
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Membrane Proteins / metabolism
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Membrane Transport Proteins
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Models, Molecular
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Molecular Docking Simulation
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Molecular Structure
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Polyethylene Glycols
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Protein Conformation
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Rats
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Rats, Wistar
Substances
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2-azetidinone
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Azetidines
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Biomarkers
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Hypolipidemic Agents
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Lipids
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Membrane Proteins
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Membrane Transport Proteins
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NPC1L1 protein, human
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Polyethylene Glycols
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Ezetimibe
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tyloxapol