title: SAR studies of acidic dual γ-secretase/PPARγ modulators.
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.
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Hieke
authors.forename: Julia
authors.initials: J
authors.lastname: Ness
authors.forename: Ramona
authors.initials: R
authors.lastname: Steri
authors.forename: Christine
authors.initials: C
authors.lastname: Greiner
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.forename: Manfred
authors.initials: M
authors.lastname: Schubert-Zsilavecz
authors.forename: Sascha
authors.initials: S
authors.lastname: Weggen
authors.forename: Heiko
authors.initials: H
authors.lastname: Zettl
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002208:Caproates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D006224:Cricetinae; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008968:Molecular Conformation; D047495:PPAR gamma / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012756:Sheep; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D002208:Caproates; D016861:Cyclooxygenase Inhibitors; D047495:PPAR gamma; D011994:Recombinant Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D053829:Amyloid Precursor Protein Secretases