title: NSAID-derived γ-secretase modulation requires an acidic moiety on the carbazole scaffold.
abstract: Modulation of γ-secretase activity holds potential for the treatment of Alzheimer's disease. Most NSAID-derived γ-secretase modulators feature a carboxylic acid, which may impair blood-brain barrier permeation. The structure activity relationship of 33 carbazoles featuring diverse carboxylic acid isosteres or metabolic precursors thereof was established in a cellular amyloid secretion assay. The modulatory activity was observed for acidic moieties and metabolically labile esters only, which supports our hypothesis of an acid-lysine interaction to be relevant for this type of γ-secretase modulators.
authors.affiliation: Clemens Schöpf-Institute of Chemistry and Biochemistry, Technische Universität Darmstadt, Petersenstr. 22, Darmstadt D-64287, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Zall
authors.forename: Daniel
authors.initials: D
authors.lastname: Kieser
authors.forename: Nicole
authors.initials: N
authors.lastname: Höttecke
authors.forename: Eva C
authors.initials: EC
authors.lastname: Naumann
authors.forename: Binia
authors.initials: B
authors.lastname: Thomaszewski
authors.forename: Katrin
authors.initials: K
authors.lastname: Schneider
authors.forename: Dirk T
authors.initials: DT
authors.lastname: Steinbacher
authors.forename: Robert
authors.initials: R
authors.lastname: Schubenel
authors.forename: Stefan
authors.initials: S
authors.lastname: Masur
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Baumann
authors.forename: Boris
authors.initials: B
authors.lastname: Schmidt
mesh_terms: D000143:Acids / Q000138:chemical synthesis / Q000737:chemistry; D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000187:drug effects; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000032:analysis / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002227:Carbazoles / Q000032:analysis / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002264:Carboxylic Acids / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D011345:Fenofibrate / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D013329:Structure-Activity Relationship
chemical_list: C545487:APP protein, human; D000143:Acids; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002227:Carbazoles; D002264:Carboxylic Acids; D053829:Amyloid Precursor Protein Secretases; D011345:Fenofibrate