2. Academic Validation
  3. Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer's disease

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

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

Affiliation

  • 1 Chemical and Screening Sciences, and Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, New Jersey 08543, USA. mayers@wyeth.com
PMID: 19012391 DOI: 10.1021/jm801252w
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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