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
  • 1. Chemical and Screening Sciences, and Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, New Jersey 08543, USA. [email protected]
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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