Design, synthesis, and biological evaluation of a novel class of gamma-secretase modulators with PPARgamma activity.

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Hieke M, Ness J, Steri R, Dittrich M, Greiner C, Werz O, Baumann K, Schubert-Zsilavecz M, Weggen S, Zettl H

Design, synthesis, and biological evaluation of a novel class of gamma-secretase modulators with PPARgamma activity.

J Med Chem. 2010 Jun 24;53(12):4691-700. doi: 10.1021/jm1003073.

PubMed ID

20503989 [ View in PubMed

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Abstract

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).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Carprofen	Prostaglandin G/H synthase 2	IC 50 (nM)	100	N/A	N/A	Details
Ibuprofen	Prostaglandin G/H synthase 2	IC 50 (nM)	80000	N/A	N/A	Details
Indomethacin	Prostaglandin G/H synthase 2	IC 50 (nM)	10	N/A	N/A	Details