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
Chemical and Screening Sciences, and Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, New Jersey 08543, USA.
J Med Chem. 2008 Dec 11;51(23):7348-51. doi: 10.1021/jm801252w.
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.
对高通量筛选命中化合物1和2进行的构效关系研究产生了强效的、对Notch-1无抑制作用的γ-分泌酶抑制剂9，该化合物以100 mg/kg的口服剂量降低了Tg2576小鼠脑中的β-淀粉样蛋白水平。将9中代谢不稳定的甲基转化为三氟甲基，得到了更稳定的类似物10，其体内活性有所提高。进一步对侧链进行修饰得到了强效的、对Notch-1无抑制作用的γ-分泌酶抑制剂贝加司他（5），该化合物被选用于治疗阿尔茨海默病的研发。
