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Discovery of Begacestat, a Notch-1-sparing Gamma-Secretase Inhibitor for the Treatment of Alzheimer's Disease

Scott C Mayer, Anthony F Kreft, Boyd Harrison, Magid Abou-Gharbia, Madelene Antane, Suzan Aschmies, Kevin Atchison, Michael Chlenov, Derek C Cole, Thomas Comery, George Diamantidis, John Ellingboe, Kristi Fan, etc.

J Med Chem. 2008 Dec 11;51(23):7348-51.

PMID: 19012391

Abstract:

SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg2576 mice at 100 mg/kg po. Converting the metabolically labile methyl groups in 9 to trifluoromethyl groups afforded the more stable analogue 10, which had improved in vivo potency. Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5), which was selected for development for the treatment of Alzheimer's disease.

Chemicals Related in the Paper:

Catalog Number Product Name Structure CAS Number Price
AP769169279 Begacestat Begacestat 769169-27-9 Price
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