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- W2006568013 abstract "We present a novel class of dual modulators of γ-secretase and peroxisome proliferator-activated receptor γ (PPARγ) based on the structure of 2-(bis(phenethoxy)pyrimidine-2-ylthio)hexanoic acid 8 (IC50(Aβ42) = 22.8 μM, EC50(PPARγ) = 8.3 μM). The modulation of both targets with approved drugs (i.e., amyloid-β 42 (Aβ42)-lowering NSAIDs for γ-secretase and glitazones for PPARγ) has demonstrated beneficial effects in in vitro and in vivo models of Alzheimer’s disease (AD). However, although NSAIDs and PPARγ agonists share similar structural features, no druglike compounds with dual activities as γ-secretase modulators (GSMs) and PPARγ agonists have been designed so far. On the basis of our initial lead structure 8, we present the structure−activity relationships (SARs) of broad structural variations. A significant improvement was reached by the introduction of p-trifluoromethyl substituents at the phenyl residues yielding compound 16 (IC50(Aβ42) = 6.0 μM, EC50(PPARγ) = 11.0 μM) and the replacement of the two phenyl residues of 8 by cyclohexyl yielding compound 22 (IC50(Aβ42) = 5.1 μM, EC50(PPARγ) = 6.6 μM)." @default.
- W2006568013 created "2016-06-24" @default.
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- W2006568013 date "2010-05-26" @default.
- W2006568013 modified "2023-10-17" @default.
- W2006568013 title "Design, Synthesis, and Biological Evaluation of a Novel Class of γ-Secretase Modulators with PPARγ Activity" @default.
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- W2006568013 doi "https://doi.org/10.1021/jm1003073" @default.
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