Abstract
A novel class of benzocinnolinones analogs of irdabisant were designed and synthesized as histamine H3R antagonists/inverse agonists. Modifications to the pyridazinone portion of the core and linker led to the identification of molecules with excellent target potency and selectivity with improved rat pharmacokinetic properties and reduced potential hERG liabilities.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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CHO Cells
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Cell Membrane / drug effects
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Cell Membrane / metabolism
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Cricetinae
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Dose-Response Relationship, Drug
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Drug Inverse Agonism
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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / pharmacology
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Histamine Agonists / chemical synthesis*
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Histamine Agonists / pharmacology
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Histamine H3 Antagonists / chemical synthesis*
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Histamine H3 Antagonists / pharmacology
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Molecular Structure
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Nootropic Agents / chemical synthesis*
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Nootropic Agents / pharmacology
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Pyridazines / chemical synthesis*
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Pyridazines / pharmacology
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Pyrrolidines / chemical synthesis*
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Pyrrolidines / pharmacology
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Rats
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Receptors, Histamine H3 / chemistry*
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Receptors, Histamine H3 / metabolism
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Structure-Activity Relationship
Substances
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Heterocyclic Compounds, 3-Ring
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Histamine Agonists
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Histamine H3 Antagonists
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Nootropic Agents
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Pyridazines
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Pyrrolidines
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Receptors, Histamine H3
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6-(4-(3-(2-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-pyridazin-3-one