Stem Cell Mobilizers Targeting Chemokine Receptor CXCR4: Renoprotective Application in Acute Kidney Injury

We have discovered a novel series of quinazoline-based CXCR4 antagonists. Of these, compound 19 mobilized CXCR4+ cell types, including hematopoietic stem cells and endothelial progenitor cells, more efficiently than the marketed 1 (AMD3100) with subcutaneous administration at the same dose (6 mg/kg)...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2015-03, Vol.58 (5), p.2315-2325
Main Authors: Wu, Chien-Huang, Song, Jen-Shin, Chang, Kuei-Hua, Jan, Jiing-Jyh, Chen, Chiung-Tong, Chou, Ming-Chen, Yeh, Kai-Chia, Wong, Ying-Chieh, Tseng, Chen-Tso, Wu, Szu-Huei, Yeh, Ching-Fang, Huang, Chung-Yu, Wang, Min-Hsien, Sadani, Amit A, Chang, Chun-Ping, Cheng, Chia-Yi, Tsou, Lun K, Shia, Kak-Shan
Format: Article
Language:English
Subjects:
Acute Kidney Injury - prevention & control
Animals
Chemotaxis - drug effects
Flow Cytometry
Hematopoietic Stem Cell Mobilization
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - metabolism
Humans
Male
Mice
Mice, Inbred C57BL
Quinazolines - chemistry
Quinazolines - pharmacology
Rats
Receptors, CXCR4 - antagonists & inhibitors
Reperfusion Injury - prevention & control
Signal Transduction
Triazoles - chemistry
Triazoles - pharmacology
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Summary:We have discovered a novel series of quinazoline-based CXCR4 antagonists. Of these, compound 19 mobilized CXCR4+ cell types, including hematopoietic stem cells and endothelial progenitor cells, more efficiently than the marketed 1 (AMD3100) with subcutaneous administration at the same dose (6 mg/kg) in mice. This series of compounds thus provides a set of valuable tools to study diseases mediated by the CXCR4/SDF-1 axis, including myocardial infarction, ischemic stroke, and cancer metastasis. More importantly, treatment with compound 19 significantly lowered levels of blood urea nitrogen and serum creatinine in rats with renal ischemia-reperfusion injury, providing evidence for its therapeutic potential in preventing ischemic acute kidney injury. CXCR4 antagonists such as 19 might also be useful to increase circulating levels of adult stem cells, thereby exerting beneficial effects on damaged and/or inflamed tissues in diseases that currently are not treated by standard approaches.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm501769r