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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

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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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