作者
Scott C. Mayer,Anthony F. Kreft,Boyd L. Harrison,Magid Abou‐Gharbia,Madelene Antane,Suzan Aschmies,Kevin Atchison,Michael Chlenov,Derek C. Cole,Thomas A. Comery,George Diamantidis,John W. Ellingboe,Kristi Fan,Rocco J. Galante,Cathleen Gonzales,Douglas M. Ho,Molly E. Hoke,Yun Hu,Donna M. Huryn,Uday Jain,Mei Jin,Kenneth Kremer,Dennis Kubrak,Melissa Lin,Peter J. Lu,R. L. Magolda,Robert Martone,William Moore,Aram Oganesian,Menelas N. Pangalos,Annalena La Porte,Peter H. Reinhart,Lauren B. Resnick,David Riddell,June Sonnenberg‐Reines,Joseph R. Stock,Shaiu-Ching Sun,Erik Wagner,Ting Wang,Kevin R. Woller,Zheng Xu,Margaret M. Zaleska,Joseph Zeldis,Minsheng Zhang,Hua Zhou,J. Steven Jacobsen
摘要
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.