Discovery of a Novel, Orally Efficacious Liver X Receptor (LXR) β Agonist

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• 作者：Yajun Zheng ; Linghang Zhuang ; Kristi Yi Fan ; Colin M. Tice ; Wei Zhao ; Chengguo Dong ; Stephen D. Lotesta ; Katerina Leftheris ; Peter R. Lindblom ; Zhijie Liu ; Jun Shimada ; Paul B. Noto ; Shi Meng ; Andrew Hardy ; Lamont Howard ; Paula Krosky ; Joan Guo ; Kerri Lipinski ; Geeta Kandpal ; Yuri Bukhtiyarov ; Yi Zhao ; Deepak Lala ; Rebecca Van Orden ; Jing Zhou ; Guozhou Chen ; Zhongren Wu ; Brian M. McKeever ; Gerard M. McGeehan ; Richard E. Gregg ; David A. Claremon ; Suresh B. Singh
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：59
• 期：7
• 页码：3264-3271
• 全文大小：445K
• 年卷期：0
• ISSN：1520-4804

文摘

This article describes the application of Contour to the design and discovery of a novel, potent, orally efficacious liver X receptor β (LXRβ) agonist (17). Contour technology is a structure-based drug design platform that generates molecules using a context perceptive growth algorithm guided by a contact sensitive scoring function. The growth engine uses binding site perception and programmable growth capability to create drug-like molecules by assembling fragments that naturally complement hydrophilic and hydrophobic features of the protein binding site. Starting with a crystal structure of LXRβ and a docked 2-(methylsulfonyl)benzyl alcohol fragment (6), Contour was used to design agonists containing a piperazine core. Compound 17 binds to LXRβ with high affinity and to LXRα to a lesser extent, and induces the expression of LXR target genes in vitro and in vivo. This molecule served as a starting point for further optimization and generation of a candidate which is currently in human clinical trials for treating atopic dermatitis.