Scaffold of the cyclooxygenase-2 (COX-2) inhibitor carprofen provides Alzheimer gamma-secretase modulators.
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.
Narlawar
Rajeshwar
R
Clemens Schöpf-Institute of Chemistry and Biochemistry, Darmstadt University of Technology, Petersenstrasse 22, D-64287 Darmstadt, Germany.
Pérez Revuelta
Blanca I
BI
Haass
Christian
C
Steiner
Harald
H
Schmidt
Boris
B
Baumann
Karlheinz
K
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
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