Discovery of SCH 900229, a Potent Presenilin 1 Selective 纬-Secretase Inhibitor for the Treatment of Alzheimer鈥檚 Disease

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• 作者：Wen-Lian Wu ; Martin Domalski ; Duane A. Burnett ; Hubert Josien ; Thomas Bara ; Murali Rajagopalan ; Ruo Xu ; John Clader ; William J. Greenlee ; Andrew Brunskill ; Lynn A. Hyde ; Robert A. Del Vecchio ; Mary E. Cohen-Williams ; Lixin Song ; Julie Lee ; Giuseppe Terracina ; Qi Zhang ; Amin Nomeir ; Eric M. Parker ; Lili Zhang
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：November 8, 2012
• 年：2012
• 卷：3
• 期：11
• 页码：892-896
• 全文大小：315K
• 年卷期：v.3,no.11(November 8, 2012)
• ISSN：1948-5875

文摘

An exploration of the SAR of the side chain of a novel tricyclic series of 纬-secretase inhibitors led to the identification of compound (鈭?-16 (SCH 900229), which is a potent and PS1 selective inhibitor of 纬-secretase (A尾40 IC₅₀ = 1.3 nM). Compound (鈭?-16 demonstrated excellent lowering of A尾 after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer鈥檚 disease.

Keywords:

纬-Secretase inhibitor; Alzheimer鈥檚 disease; amyloid; notch; clinical candidate