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
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , Miaoli, Miaoli County 35053, Taiwan R.O.C.
J Med Chem. 2015 Mar 12;58(5):2315-25. doi: 10.1021/jm501769r. Epub 2015 Mar 2.
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.
我们发现了一系列新型的基于喹唑啉的CXCR4拮抗剂。其中，化合物19在小鼠中以相同剂量（6毫克/千克）皮下给药时，比市售的1（AMD3100）更有效地动员了CXCR4(+)细胞类型，包括造血干细胞和内皮祖细胞。因此，这一系列化合物为研究由CXCR4/SDF-1轴介导的疾病提供了一套有价值的工具，这些疾病包括心肌梗死、缺血性中风和癌症转移。更重要的是，用化合物19治疗可显著降低肾缺血再灌注损伤大鼠的血尿素氮和血清肌酐水平，为其预防缺血性急性肾损伤的治疗潜力提供了证据。像19这样的CXCR4拮抗剂可能也有助于提高成体干细胞的循环水平，从而对目前标准方法无法治疗的疾病中受损和/或发炎的组织产生有益影响。
