Abstract
A novel class of 1'-cyclobutyl-6-(4-piperidyloxy)spiro[benzopyran-2,4'-piperidine] derivatives with low nanomolar affinity for the human and rat histamine-3 receptors (H(3)Rs) are described. The spirobenzopyran piperidine ether analogs demonstrated excellent H(3)R affinity and selectivity against histamine receptor subtypes (H(1)R, H(2)R, and H(4)R), were stable in liver microsomes, and had selectivity against CYP P450 enzymes. Compounds 10, 13, 15, and 16 demonstrated high H(3)R affinity, in vitro liver microsomal stability, selectivity against CYP isoforms, moreover, these ether analogs exhibited acceptable iv pharmacokinetic (PK) properties but had poor oral exposure in rat.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Benzopyrans / chemical synthesis*
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Benzopyrans / pharmacokinetics
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Benzopyrans / pharmacology
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Cytochrome P-450 Enzyme System / metabolism
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Histamine Antagonists / chemical synthesis*
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Histamine Antagonists / pharmacokinetics
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Histamine Antagonists / pharmacology
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Humans
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Injections, Intravenous
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Piperidines / chemical synthesis*
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Piperidines / pharmacokinetics
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Piperidines / pharmacology
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Rats
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Receptors, Histamine H3 / metabolism*
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Spiro Compounds / chemical synthesis*
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Spiro Compounds / pharmacokinetics
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Spiro Compounds / pharmacology
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Structure-Activity Relationship
Substances
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Benzopyrans
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Histamine Antagonists
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Piperidines
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Receptors, Histamine H3
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Spiro Compounds
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Cytochrome P-450 Enzyme System