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-(tri

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• 作者：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 ; Fr茅d茅rique Bard ; Michael P. Bova ; Susanna S. Hemphill ; Lam Nguyen ; Lany Ruslim ; Kevin Tanaka ; Pearl Tanaka ; William Wallace ; Ted A. Yednock ; Guriqbal S. Basi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 11, 2013
• 年：2013
• 卷：56
• 期：13
• 页码：5261-5274
• 全文大小：621K
• 年卷期：v.56,no.13(July 11, 2013)
• ISSN：1520-4804

文摘

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