Design, synthesis, and biological evaluation of a novel class of gamma-secretase modulators with PPARgamma activity.
We present a novel class of dual modulators of gamma-secretase and peroxisome proliferator-activated receptor gamma (PPARgamma) based on the structure of 2-(bis(phenethoxy)pyrimidine-2-ylthio)hexanoic acid 8 (IC(50)(Abeta42) = 22.8 microM, EC(50)(PPARgamma) = 8.3 microM). The modulation of both targets with approved drugs (i.e., amyloid-beta 42 (Abeta42)-lowering NSAIDs for gamma-secretase and glitazones for PPARgamma) has demonstrated beneficial effects in in vitro and in vivo models of Alzheimer's disease (AD). However, although NSAIDs and PPARgamma agonists share similar structural features, no druglike compounds with dual activities as gamma-secretase modulators (GSMs) and PPARgamma 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 (IC(50)(Abeta42) = 6.0 microM, EC(50)(PPARgamma) = 11.0 microM) and the replacement of the two phenyl residues of 8 by cyclohexyl yielding compound 22 (IC(50)(Abeta42) = 5.1 microM, EC(50)(PPARgamma) = 6.6 microM).
Hieke
Martina
M
Institute of Pharmaceutical Chemistry, ZAFES/LiFF/Goethe University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
Ness
Julia
J
Steri
Ramona
R
Dittrich
Michaela
M
Greiner
Christine
C
Werz
Oliver
O
Baumann
Karlheinz
K
Schubert-Zsilavecz
Manfred
M
Weggen
Sascha
S
Zettl
Heiko
H
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002208:Caproates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D012756:Sheep; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects
D016229:Amyloid beta-Peptides; D002208:Caproates; D016861:Cyclooxygenase Inhibitors; D047495:PPAR gamma; D010446:Peptide Fragments; D011743:Pyrimidines; D051880:Receptors, Notch; C078639:amyloid beta-protein (1-38); C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases