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 gamma-Secretase Inhibitors that Selectively Inhibit the Production of Amyloid-beta over Notch

作者：Probst Gary^*; Aubele Danielle L; Bowers Simeon; Dressen Darren; Garofalo Albert W; Horn Roy K; Konradi Andrei W; Marugg Jennifer L; Mattson Matthew N; Neitzel Martin L; Semko Chris M; Sham Hing L; Smith Jenifer; Sun Minghua; Truong Anh P; Ye Xiaocong M; Xu Ying zi; Dappen Michael S; Jagodzinski Jacek J; Keim Pamela S; Peterson Brian; Latimer Lee H; Quincy David; Wu Jing; Goldbach Erich; Ness Daniel K; Quinn Kevin P; Sauer John Michael; Wong Karina

来源：Journal of Medicinal Chemistry, 2013, 56(13): 5261-5274.

DOI：10.1021/jm301741t

Herein, we describe our strategy to design metabolically stable gamma-secretase inhibitors which are selective for inhibition of A beta 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 A beta generation in vivo between 30, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered A in the CSF of healthy human volunteers.

• 出版日期2013-7-11