Abstract
Analogs of the known H(1)-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study.
Copyright © 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Cytochrome P-450 CYP2D6 / metabolism
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Dimethindene / chemistry
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Electroencephalography
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Histamine H1 Antagonists / chemistry*
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Histamine H1 Antagonists / pharmacokinetics
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Histamine H1 Antagonists / therapeutic use
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Humans
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Indenes / chemistry*
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Indenes / pharmacokinetics
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Indenes / therapeutic use
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Microsomes, Liver / metabolism
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Models, Animal
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Pyridazines / chemistry*
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Pyridazines / pharmacokinetics
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Pyridazines / therapeutic use
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Rats
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Receptors, Histamine H1 / chemistry*
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Receptors, Histamine H1 / metabolism
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Sleep Initiation and Maintenance Disorders / drug therapy*
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Structure-Activity Relationship
Substances
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Histamine H1 Antagonists
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Indenes
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Pyridazines
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Receptors, Histamine H1
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Dimethindene
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indene
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Cytochrome P-450 CYP2D6