Design, Synthesis, and Biological Evaluation of a Novel Class of γ-Secretase Modulators with PPARγ Activity

We present a novel class of dual modulators of gamma-secretase and peroxisome proliferator-activated receptor gamma (PPAR gamma) based on the structure of 2-(bis(phenethoxy)pyrimidine-2-ylthio)hexanoic acid 8 (IC50(A beta 42) = 22.8 mu M, EC50(PPAR gamma) = 8.3 mu M). The modulation of both targets with approved drugs (i.e., amyloid-beta 42 (A beta 42)-lowering NSAIDs for gamma-secretase and glitazones for PPAR gamma) has demonstrated beneficial effects in in vitro and in vivo models of Alzheimer's disease (AD). However, although NSAIDs and PPAR gamma agonists share similar structural features, no druglike compounds with dual activities as gamma-secretase modulators (GSMs) and PPAR gamma 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(A beta 42) = 6.0 mu M, EC50(PPAR gamma) = 11.0 mu M) and the replacement of the two phenyl residues of 8 by cyclohexyl yielding compound 22 (IC50(A beta 42) = 5.1 mu M, EC50(PPAR gamma) = 6.6 mu M).