Abstract
Attempts to block metabolism by incorporating a 9-fluoro substituent at the A-ring of compound 1 (SCH 900229) using electrophilic Selectfluor™ led to an unexpected oxidation of the A-ring to give difluoroquinone analog 1a. Oxidation of other related chromene γ-secretase inhibitors 2-8 resulted in similar difluoroquinone analogs 2a-8a, respectively. These quinone products exhibited comparable in vitro potency in a γ-scretase membrane assay, but were several fold less potent in a cell-based assay in lowering Aβ40-42, compared to their parent compounds.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Benzopyrans / chemical synthesis
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Benzopyrans / chemistry*
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Benzopyrans / pharmacology
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Benzoquinones / chemical synthesis
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Benzoquinones / chemistry
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Benzoquinones / pharmacology
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Enzyme Activation / drug effects
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Fluorine / chemistry
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Fluorine / pharmacology
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Humans
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Molecular Structure
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Oxidation-Reduction
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Sulfones / chemical synthesis
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Sulfones / chemistry*
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Sulfones / pharmacology
Substances
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Benzopyrans
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Benzoquinones
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Enzyme Inhibitors
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SCH 900229
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Sulfones
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Fluorine
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quinone
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Amyloid Precursor Protein Secretases