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. 2008 Dec 11;51(23):7348-51.
doi: 10.1021/jm801252w.

Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer's disease

Scott C Mayer  1 , 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, Rocco Galante, Cathleen Gonzales, Douglas M Ho, Molly E Hoke, Yun Hu, Donna Huryn, Uday Jain, Mei Jin, Kenneth Kremer, Dennis Kubrak, Melissa Lin, Peimin Lu, Ron Magolda, Robert Martone, William Moore, Aram Oganesian, Menelas N Pangalos, Alex Porte, Peter Reinhart, Lynn Resnick, David R Riddell, June Sonnenberg-Reines, Joseph R Stock, Shaiu-Ching Sun, Erik Wagner, Ting Wang, Kevin Woller, Zheng Xu, Margaret M Zaleska, Joseph Zeldis, Minsheng Zhang, Hua Zhou, J Steven Jacobsen
Affiliations

Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer's disease

Scott C Mayer et al. J Med Chem. .

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.

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