Abstract
The discovery and optimization of imidazole cyclopropyl amime analogues as mutant IDH1 inhibitors via structure-based rational design were reported. The optimal compounds demonstrated both potent inhibition in IDH1R132H enzymatic activity and 2HG production in IDH1 mutant HT1080 cell line, moderate liver microsome stability and PK properties.
Keywords:
IDH1 inhibitor; Imidazole cyclopropyl amine; Structure-based rational design.
Copyright © 2018. Published by Elsevier Ltd.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amines / chemistry
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Amines / metabolism
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Amines / pharmacokinetics
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Amines / pharmacology
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Animals
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Cell Line
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Drug Design*
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Drug Discovery
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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Humans
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Imidazoles / chemistry*
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Imidazoles / metabolism
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Imidazoles / pharmacokinetics
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Imidazoles / pharmacology*
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Isocitrate Dehydrogenase / antagonists & inhibitors*
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Isocitrate Dehydrogenase / genetics
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Isocitrate Dehydrogenase / metabolism
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Mice
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Microsomes, Liver / metabolism
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Molecular Docking Simulation
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Mutation
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Rats
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Structure-Activity Relationship
Substances
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Amines
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Enzyme Inhibitors
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Imidazoles
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Isocitrate Dehydrogenase
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IDH1 protein, human