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

…, M Abou-Gharbia, M Antane, S Aschmies…

Index: Mayer, Scott C.; Kreft, Anthony F.; Harrison, Boyd; Abou-Gharbia, Magid; Antane, Madelene; Aschmies, Suzan; Atchison, Kevin; Chlenov, Michael; Cole, Derek C.; Comery, Thomas; Diamantidis, George; Ellingboe, John; Fan, Kristi; Galante, Rocco; Gonzales, Cathleen; Ho, Douglas M.; Hoke, Molly E.; Hu, Yun; Huryn, Donna; Jain, Uday; Jin, Mei; Kremer, Kenneth; Kubrak, Dennis; Lin, Melissa; Lu, Peimin; Magolda, Ron; Martone, Robert; Moore, William; Oganesian, Aram; Pangalos, Menelas N.; Porte, Alex; Reinhart, Peter; Resnick, Lynn; Riddell, David R.; Sonnenberg-Reines, June; Stock, Joseph R.; Sun, Shaiu-Ching; Wagner, Erik; Wang, Ting; Woller, Kevin; Xu, Zheng; Zaleska, Margaret M.; Zeldis, Joseph; Zhang, Minsheng; Zhou, Hua; Jacobsen, J. Steven Journal of Medicinal Chemistry, 2008 , vol. 51, # 23 p. 7348 - 7351

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Citation Number: 88

Abstract

SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Aβ 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.