NSAID-derived gamma-secretase modulators. Part III: Membrane anchoring.
Selective lowering of Abeta(42) levels with small-molecule substrate targeting gamma-secretase modulators (sGSMs), such as some non-steroidal anti-inflammatory drugs, is a promising therapeutic approach for Alzheimer's disease. Here we present N-substituted carbazole- and O-substituted fenofibrate-derived sGSMs and their activity data. Seven out of 19 screened compounds exhibited promising activity against Abeta(42) secretion at a low micromolar level. We presume that the sGSMs interact with lys624 at the membrane interface and that the lipophilic substituents anchor the compound orientation in the membrane.
Baumann
Stefanie
S
Clemens Schöpf-Institute of Chemistry and Biochemistry, Technische Universität Darmstadt, Petersenstr. 22, D-64287 Darmstadt, Germany.
Höttecke
Nicole
N
Schubenel
Robert
R
Baumann
Karlheinz
K
Schmidt
Boris
B
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002227:Carbazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D011345:Fenofibrate / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002227:Carbazoles; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; C007005:carprofen; D011345:Fenofibrate