Abstract
Synthesis, SAR, and evaluation of aryl triazoles as novel gamma secretase modulators (GSMs) are presented in this communication. Starting from the literature and in-house leads, we evaluated a range of five-membered heterocycles as replacements for olefins commonly found in non-acid GSMs. 1,2,3-C-aryl-triazoles were identified as suitable replacements which exhibited good modulation of γ-secretase activity, excellent pharmacokinetics and good central lowering of Aβ42 in Sprague-Dawley rats.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Amyloid Precursor Protein Secretases / metabolism*
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Amyloid beta-Peptides / metabolism
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Animals
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Enzyme Activation / drug effects
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Inhibitory Concentration 50
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Molecular Structure
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Protein Binding
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Triazoles / chemical synthesis*
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Triazoles / metabolism
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Triazoles / pharmacology*
Substances
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Amyloid beta-Peptides
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Enzyme Inhibitors
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Triazoles
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Amyloid Precursor Protein Secretases