title: N-Substituted carbazolyloxyacetic acids modulate Alzheimer associated gamma-secretase.
abstract: N-Sulfonylated and N-alkylated carbazolyloxyacetic acids were investigated for the inhibition and modulation of the Alzheimer's disease associated gamma-secretase. The introduction of a lipophilic substituent, which may vary from arylsulfone to alkyl, turned 2-carbazolyloxyacetic acids into potent gamma-secretase modulators. This resulted in the selective reduction of Abeta(42) and an increase of the less aggregatory Abeta(38) fragment by several compounds (e.g., 7d and 8c). Introduction of an electron donating group at position 6 and 8 of N-substituted carbazolyloxyacetic acids either decreased the activity or inversed modulation. The most active compounds displayed activity on amyloid precursor protein (APP) overexpressing cell lines in the low micromolar range and little or no effect on the gamma-secretase cleavage at the epsilon-site.
authors.affiliation: Clemens Schöpf-Institute of Chemistry and Biochemistry, Darmstadt University of Technology, Petersenstr. 22, D-64287 Darmstadt, Germany.
authors.forename: Rajeshwar
authors.initials: R
authors.lastname: Narlawar
authors.forename: Blanca I
authors.initials: BI
authors.lastname: Pérez Revuelta
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Baumann
authors.forename: Robert
authors.initials: R
authors.lastname: Schubenel
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.forename: Harald
authors.initials: H
authors.lastname: Steiner
authors.forename: Boris
authors.initials: B
authors.lastname: Schmidt
mesh_terms: D000085:Acetates / Q000737:chemistry* / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects*; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors*; D006801:Humans
chemical_list: D000085:Acetates; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases