Discovery of CNS Penetrant CXCR2 Antagonists for the Potential Treatment of CNS Demyelinating Disorders

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• 作者：Heng Xu ; Hongfu Lu ; Zhongmiao Xu ; Linbo Luan ; Chengyong Li ; Yan Xu ; Kelly Dong ; Jinqiang Zhang ; Xiong Li ; Yvonne Li ; Gentao Liu ; Sophie Gong ; Yong-Gang Zhao ; Ailian Liu ; Yueting Zhang ; Wei Zhang ; Xin Cai ; Jia-Ning Xiang ; John D. Elliott ; Xichen Lin
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：7
• 期：4
• 页码：397-402
• 全文大小：342K
• 年卷期：0
• ISSN：1948-5875

文摘

Structure–activity relationship exploration of the historical biarylurea series led to the identification of novel CNS penetrant CXCR2 antagonists with nanomolar potency, favorable PK profile, and good developability potentials. More importantly, the key compound 22 showed efficacy in a cuprizone-induced demyelination model with twice daily oral administration, thereby supporting CXCR2 to be a potential therapeutic target for the treatment of demyelinating diseases such as multiple sclerosis.