Abstract
This Letter describes the synthesis and structure-activity-relationships (SAR) of isoform-selective PLD inhibitors. By virtue of the installation of alternative halogenated piperidinyl benzimidazolone privileged structures, in combination with a key (S)-methyl group, novel PLD inhibitors with low nM potency and unprecedented levels of PLD1 isoform selectivity (approximately 1700-fold) over PLD2 were developed.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Benzimidazoles / chemical synthesis*
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Benzimidazoles / chemistry
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Benzimidazoles / pharmacology
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Cell Line
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Domperidone / analogs & derivatives*
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Domperidone / chemical synthesis
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Domperidone / chemistry
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Domperidone / pharmacology
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Halogenation
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Humans
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Phospholipase D / antagonists & inhibitors*
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Phospholipase D / metabolism
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / metabolism
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Structure-Activity Relationship
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Substrate Specificity
Substances
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Benzimidazoles
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Enzyme Inhibitors
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Protein Isoforms
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benzimidazolone
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Domperidone
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Phospholipase D
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phospholipase D1