Development of CXCR4 modulators based on the lead compound RB-108

• Type of Material: Article
• Authors: Renren Bai, Zhejiang University of Technology; Xiaokang Jie, Zhejiang University of Technology; Jian Sun, Zhejiang University of Technology; Zhongxing Liang, Emory University; Younghyoun Yoon, Emory University; Amber Feng, Emory University; Yoonhyeun Oum, Emory University; Wenyan Yu, Zhejiang University of Technology; Rui Wu, Zhejiang University of Technology; Bin Sun, Zhejiang University of Technology; Eric Salgado, Emory University; Yuanyuan Xie, Zhejiang University of Technology; Hyunsuk Shim, Emory University
• Language: English
• Date: 2019-07-01
• Publisher: Elsevier Science Ltd.
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 Elsevier Masson SAS. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ejmech.2019.03.065
• Title of Journal or Parent Work: European Journal of Medicinal Chemistry
• Volume: 173
• Start Page: 32
• End Page: 43
• Grant/Funding Information: This study was financially supported by the National Natural Science Foundation of China, NSFC (Grant No. 81803340), Zhejiang Provincial Department of Education (Grant No. Y201840109) and NIH NCI (R01 CA165306).
• Keywords: Inflammatory cell recruitment; Pharmacology & Pharmacy; Selectivity; CXCR4 modulators; Structural modification; Anti-inflammation; Chemokine receptor; Chemistry, Medicinal; Amines; RB-108; Life Sciences & Biomedicine; Science & Technology
• Research Categories: Biology, Cell; Chemistry, Biochemistry; Health Sciences, Immunology; Health Sciences, Pharmacology

Abstract

The CXCR4/CXCL12 axis plays prominent roles in tumor metastasis and inflammation. CXCR4 has been shown to be involved in a variety of inflammation-related diseases. Therefore, CXCR4 is a promising potential target to develop novel anti-inflammatory agents. Taking our previously discovered CXCR4 modulator RB-108 as the lead compound, a series of derivatives were synthesized structurally modifying and optimizing the amide and sulfamide side chains. The derivatives successfully maintained potent CXCR4 binding affinity. Furthermore, compounds IIb, IIc, IIIg, IIIj, and IIIm were all efficacious in inhibiting the invasion of CXCR4-positive cells, displaying a much more potent effect than the lead compound RB-108. Notably, compound IIIm significantly decreased carrageenan-induced swollen volume and paw thickness in a mouse paw edema model. More importantly, IIIm exhibited satisfying PK profiles with a half-life of 4.77 h in an SD rat model. In summary, we have developed compound IIIm as a new candidate for further investigation based on the lead compound RB-108.