- Discovery of (R)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline (ELND006) and (R)-4-cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline (ELND007): metabolically stable γ-secretase Inhibitors that selectively inhibit the production of amyloid-β over Notch.
Discovery of (R)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline (ELND006) and (R)-4-cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline (ELND007): metabolically stable γ-secretase Inhibitors that selectively inhibit the production of amyloid-β over Notch.
Journal of medicinal chemistry (2013-05-30)
Gary Probst, Danielle L Aubele, Simeon Bowers, Darren Dressen, Albert W Garofalo, Roy K Hom, Andrei W Konradi, Jennifer L Marugg, Matthew N Mattson, Martin L Neitzel, Chris M Semko, Hing L Sham, Jenifer Smith, Minghua Sun, Anh P Truong, Xiaocong M Ye, Ying-Zi Xu, Michael S Dappen, Jacek J Jagodzinski, Pamela S Keim, Brian Peterson, Lee H Latimer, David Quincy, Jing Wu, Erich Goldbach, Daniel K Ness, Kevin P Quinn, John-Michael Sauer, Karina Wong, Hongbin Zhang, Wes Zmolek, Elizabeth F Brigham, Dora Kholodenko, Kang Hu, Grace T Kwong, Michael Lee, Anna Liao, Ruth N Motter, Patricia Sacayon, Pamela Santiago, Christopher Willits, Frédérique Bard, Michael P Bova, Susanna S Hemphill, Lam Nguyen, Lany Ruslim, Kevin Tanaka, Pearl Tanaka, William Wallace, Ted A Yednock, Guriqbal S Basi
PMID23713656
摘要
Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aβ generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aβ generation in vivo between 30, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered Aβ in the CSF of healthy human volunteers.