Abstract
Structure-activity relationship studies were conducted to reduce CYP2D6-mediated metabolism in a series of indene H(1)-antihistamines. Reductions in pK(a) via incorporation of a β-fluoro substituent or a heteroaryl moiety were shown to reduce contributions to metabolism through this pathway. Several compounds, including 8l, 8o, and 12f were identified with promising primary in vitro profiles and reduced biotransformation via CYP2D6.
Copyright © 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Biotransformation
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Cytochrome P-450 CYP2D6 / chemistry*
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Cytochrome P-450 CYP2D6 / metabolism
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Histamine H1 Antagonists / chemical synthesis
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Histamine H1 Antagonists / chemistry*
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Histamine H1 Antagonists / pharmacokinetics
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Indenes / chemical synthesis
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Indenes / chemistry*
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Indenes / pharmacokinetics
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Pyrazines / chemical synthesis
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Pyrazines / chemistry*
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Pyrazines / pharmacokinetics
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Receptors, Histamine H1 / chemistry*
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Receptors, Histamine H1 / metabolism
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Structure-Activity Relationship
Substances
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Histamine H1 Antagonists
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Indenes
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Pyrazines
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Receptors, Histamine H1
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Cytochrome P-450 CYP2D6