Scaffold of the cyclooxygenase-2 (COX-2) inhibitor carprofen provides Alzheimer gamma-secretase modulators.

Rajeshwar Narlawar, Blanca I Pérez Revuelta, Christian Haass, Harald Steiner, Boris Schmidt, Karlheinz Baumann

Clemens Schöpf-Institute of Chemistry and Biochemistry, Darmstadt University of Technology, Petersenstrasse 22, D-64287 Darmstadt, Germany.

Journal of medicinal chemistry 2006 Dec 28

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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.

Citation

Rajeshwar Narlawar, Blanca I Pérez Revuelta, Christian Haass, Harald Steiner, Boris Schmidt, Karlheinz Baumann. Scaffold of the cyclooxygenase-2 (COX-2) inhibitor carprofen provides Alzheimer gamma-secretase modulators. Journal of medicinal chemistry. 2006 Dec 28;49(26):7588-91