N-Substituted carbazolyloxyacetic acids modulate Alzheimer associated gamma-secretase.
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.
Narlawar
Rajeshwar
R
Clemens Schöpf-Institute of Chemistry and Biochemistry, Darmstadt University of Technology, Petersenstr. 22, D-64287 Darmstadt, Germany.
Pérez Revuelta
Blanca I
BI
Baumann
Karlheinz
K
Schubenel
Robert
R
Haass
Christian
C
Steiner
Harald
H
Schmidt
Boris
B
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
D000085:Acetates; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases