title: Scaffold of the cyclooxygenase-2 (COX-2) inhibitor carprofen provides Alzheimer gamma-secretase modulators.
abstract: N-sulfonylated and N-alkylated carprofen derivatives were investigated for their inhibition and modulation of gamma-secretase, which is associated with Alzheimer's disease. The introduction of a lipophilic substituent transformed the COX-2 inhibitor carprofen into a potent gamma-secretase modulator. Several compounds (e.g., 9p, 11f) caused selective reduction of Abeta42 and an increase of Abeta38. The most active compounds displayed activities in the low micromolar range and no effect on the gamma-secretase cleavage at the e-site.
authors.affiliation: Clemens Schöpf-Institute of Chemistry and Biochemistry, Darmstadt University of Technology, Petersenstrasse 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: 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
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Baumann
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; 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 / Q000494:pharmacology*; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000737:chemistry; D051546:Cyclooxygenase 2 / Q000737:chemistry; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D009578:Nitrobenzenes / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002227:Carbazoles; D052246:Cyclooxygenase 2 Inhibitors; D009578:Nitrobenzenes; D010446:Peptide Fragments; D013449:Sulfonamides; C078639:amyloid beta-protein (1-38); C075222:amyloid beta-protein (1-42); C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D053829:Amyloid Precursor Protein Secretases; C007005:carprofen; D007213:Indomethacin