发现可穿透中枢神经系统的CXCR2拮抗剂用于中枢神经系统脱髓鞘疾病的潜在治疗
Discovery of CNS Penetrant CXCR2 Antagonists for the Potential Treatment of CNS Demyelinating Disorders.
作者信息
Xu Heng, Lu Hongfu, Xu Zhongmiao, Luan Linbo, Li Chengyong, Xu Yan, Dong Kelly, Zhang Jinqiang, Li Xiong, Li Yvonne, Liu Gentao, Gong Sophie, Zhao Yong-Gang, Liu Ailian, Zhang Yueting, Zhang Wei, Cai Xin, Xiang Jia-Ning, Elliott John D, Lin Xichen
机构信息
State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences , 1 Xiannongtan Street, Beijing 100050, P. R. China.
Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
出版信息
ACS Med Chem Lett. 2016 Feb 8;7(4):397-402. doi: 10.1021/acsmedchemlett.5b00489. eCollection 2016 Apr 14.
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.
对历史上的联芳基脲系列进行构效关系探索，从而确定了具有纳摩尔效力、良好药代动力学特征和良好开发潜力的新型中枢神经系统渗透型CXCR2拮抗剂。更重要的是，关键化合物22在每日口服两次的情况下，在铜螯合剂诱导的脱髓鞘模型中显示出疗效，从而支持CXCR2作为治疗诸如多发性硬化症等脱髓鞘疾病的潜在治疗靶点。
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