Abstract
A series of tricyclic carboxylic acids having 6-amino-pyrimidine-2,4(1H,3H)-dione with piperazino or homopiperazino moiety linked by propylene, were synthesized and evaluated for their affinity toward human histamine H(1) receptor and Caco-2 cell permeability. Selected compounds were further evaluated for their oral anti-histaminic activity in mice, bioavailability in rats, and their anti-inflammatory activity in mice OVA-induced biphasic cutaneous reaction model. Among the compounds tested, dibenzoxazepine carboxylic acid 13b showed both histamine H(1) receptor antagonistic activity and anti-inflammatory activity in vivo. In addition, 13b exhibited low affinity toward α(1) receptor and low occupancy of H(1) receptor in the brain. It is therefore, believed that 13b is a potential candidate for development as 3rd generation anti-histamine.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Anti-Inflammatory Agents / chemical synthesis
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Anti-Inflammatory Agents / chemistry*
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Anti-Inflammatory Agents / pharmacology
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Azepines / chemical synthesis
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Azepines / chemistry
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Azepines / pharmacology
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Caco-2 Cells
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Carboxylic Acids / chemical synthesis
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Carboxylic Acids / chemistry*
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Carboxylic Acids / pharmacology
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Cell Membrane Permeability
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Cyclization
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Histamine H1 Antagonists / chemical synthesis
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Histamine H1 Antagonists / chemistry*
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Histamine H1 Antagonists / pharmacology
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Humans
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Mice
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Oxazepines / chemical synthesis
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Oxazepines / chemistry
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Oxazepines / pharmacology
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Protein Binding
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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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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Structure-Activity Relationship
Substances
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5-(3-(4-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-1,4-diazepan-1-yl)propyl)-5,11-dihydrodibenzo(b,e)(1,4)oxazepine-7-carboxylic acid
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Anti-Inflammatory Agents
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Azepines
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Carboxylic Acids
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Histamine H1 Antagonists
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Oxazepines
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Pyrimidines
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Receptors, Histamine H1