Abstract
Synthesis and biological evaluation of potent histamine H3 receptor antagonists incorporating a hydroxyl function are described. Compounds in this series exhibited nanomolar binding affinities for human receptor, illustrating a new possible component for the H3 pharmacophore. As demonstrated with compound BP1.4160 (cyclohexanol 19), the introduction of an alcohol function counter-intuitively allowed to reach high in vivo efficiency and favorable pharmacokinetic profile with reduced half-life.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Binding Sites
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Cyclohexanols / chemical synthesis
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Cyclohexanols / chemistry*
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Cyclohexanols / pharmacokinetics
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Drug Inverse Agonism
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Ethanol / chemistry*
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Half-Life
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Histamine H3 Antagonists / chemical synthesis
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Histamine H3 Antagonists / chemistry*
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Histamine H3 Antagonists / pharmacokinetics
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Humans
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Ligands*
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Male
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Mice
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Molecular Docking Simulation
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Protein Binding
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Protein Structure, Tertiary
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Receptors, Histamine H3 / chemistry*
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Receptors, Histamine H3 / genetics
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Receptors, Histamine H3 / metabolism
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
Substances
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BP1.4160
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Cyclohexanols
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Histamine H3 Antagonists
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Ligands
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Receptors, Histamine H3
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Recombinant Proteins
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Ethanol