Abstract
A novel set of dual γ-secretase/PPARγ modulators characterized by a 2-benzyl hexanoic acid scaffold is presented. Synthetic efforts were focused on the variation of the substitution pattern of the central benzene. Finally, we obtained a new class of 2,5-disubstituted 2-benzylidene hexanoic acid derivatives, which act as dual γ-secretase/PPARγ modulators in the low micromolar range. We have explored broad SAR and successfully improved the dual pharmacological activity and the selectivity profile against potential off-targets such as NOTCH and COX. Compound 17 showed an IC(50) Aβ42=2.4 μM and an EC(50) PPARγ=7.2 μM and could be a valuable tool to further evaluate the concept of dual γ-secretase/PPARγ modulators in animal models of Alzheimer's disease.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Animals
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CHO Cells
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COS Cells
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Caproates / chemical synthesis
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Caproates / chemistry
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Caproates / pharmacology*
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Cell Survival / drug effects
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Chlorocebus aethiops
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Cricetinae
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Cyclooxygenase 1 / metabolism
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Cyclooxygenase 2 / metabolism
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Cyclooxygenase Inhibitors / chemical synthesis
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Cyclooxygenase Inhibitors / chemistry
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Cyclooxygenase Inhibitors / pharmacology*
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Dose-Response Relationship, Drug
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Humans
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Molecular Conformation
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PPAR gamma / antagonists & inhibitors*
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Recombinant Proteins / antagonists & inhibitors
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Sheep
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Caproates
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Cyclooxygenase Inhibitors
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PPAR gamma
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Recombinant Proteins
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Cyclooxygenase 1
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Cyclooxygenase 2
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Amyloid Precursor Protein Secretases