Abstract
This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties.
Keywords:
Alzheimer’s disease; Benzazepine; GPCR; H(3) receptor antagonist; Histamine; Neurotransmitters.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Benzazepines / chemical synthesis
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Benzazepines / chemistry*
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Benzazepines / pharmacokinetics
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Cytochrome P-450 CYP2D6 / chemistry
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Cytochrome P-450 CYP2D6 / metabolism
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Drug Evaluation, Preclinical
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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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Microsomes, Liver / metabolism
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Protein Binding
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Rats
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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
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Structure-Activity Relationship
Substances
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Benzazepines
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Histamine H3 Antagonists
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Receptors, Histamine H3
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Recombinant Proteins
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Cytochrome P-450 CYP2D6