Brain penetrant liver X receptor (LXR) modulators based on a 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole core

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• 作者：Colin M. Tice ; Paul B. Noto ; Kristi Yi Fan ; Wei Zhao ; Stephen D. Lotesta ; Chengguo Dong ; Andrew P. Marcus ; Ya-Jun Zheng ; Guozhou Chen ; Zhongren Wu ; Rebecca Van Orden ; Jing Zhou ; Yuri Bukhtiyarov ; Yi Zhao ; Kerri Lipinski ; Lamont Howard ; Joan Guo ; Geeta Kandpal ; Shi Meng ; Andrew Hardy ; Paula Krosky ; Richard E. Gregg ; Katerina Leftheris ; Brian M. McKeever ; Suresh B. Singh ; Deepak Lala ; Gerard M. McGeehan ; Linghang Zhuang ; David A. Claremon
• 关键词：LXR ; Structure-based drug design ; Alzheimer&rsquo ; s disease ; Brain
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 October 2016
• 年：2016
• 卷：26
• 期：20
• 页码：5044-5050
• 全文大小：2210 K

文摘

Liver X receptor (LXR) agonists have been reported to lower brain amyloid beta (Aβ) and thus to have potential for the treatment of Alzheimer’s disease. Structure and property based design led to the discovery of a series of orally bioavailable, brain penetrant LXR agonists. Oral administration of compound 18 to rats resulted in significant upregulation of the expression of the LXR target gene ABCA1 in brain tissue, but no significant effect on Aβ levels was detected.