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

  • ACS Med Chem Lett. 2016 Feb 8;7(4):397-402. doi: 10.1021/acsmedchemlett.5b00489.
Heng Xu  1 ,  Hongfu Lu  2 ,  Zhongmiao Xu  2 ,  Linbo Luan  2 ,  Chengyong Li  2 ,  Yan Xu  2 ,  Kelly Dong  2 ,  Jinqiang Zhang  2 ,  Xiong Li  2 ,  Yvonne Li  2 ,  Gentao Liu  2 ,  Sophie Gong  2 ,  Yong-Gang Zhao  2 ,  Ailian Liu  2 ,  Yueting Zhang  2 ,  Wei Zhang  2 ,  Xin Cai  2 ,  Jia-Ning Xiang  2 ,  John D Elliott  2 ,  Xichen Lin  2
Affiliations
  • 1. 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.
  • 2. Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
PMID: 27096048 DOI: 10.1021/acsmedchemlett.5b00489
Abstract

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.

Keywords
CNS penetration; CXCR2 antagonists; cuprizone model; demyelinating disorders; demyelination and remyelination; diarylureas; multiple sclerosis.
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