期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 149, 期 -, 页码 30-44出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.02.042
关键词
Chemokine; CXCR4; Antagonist; GPCR; Scaffold hybridization; Therapy
资金
- National Natural Science Foundation of China [81773561, 81473090, 21502133]
- China Postdoctoral Science Foundation [2016M601884]
- Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD)
- Jiangsu Key Laboratory of Neuropsychiatric Diseases [BM2013003]
The important roles of the CXCL12/CXCR4 axis in numerous pathogenic pathways involving HIV infection and cancer metastasis make the CXCR4 receptor an attractive target for the development of therapeutic agents. Through scaffold hybridization of a few known CXCR4 antagonists, a series of novel aminopyrimidine derivatives was developed. Compound 3 from this new scaffold demonstrates excellent binding affinity with CXCR4 receptor (IC50 = 54 nM) and inhibits CXCL12 induced cytosolic calcium increase (IC50 = 2.3 nM). Furthermore, compound 3 possesses good physicochemical properties (MW 353, clogP 2.0, PSA 48, pKa 6.7) and exhibits minimal hERG and CYP isozyme (e.g. 3A4, 2D6) inhibition. Collectively, these results strongly support further optimization of this novel scaffold to develop better CXCR4 antagonists. (C) 2018 Elsevier Masson SAS. All rights reserved.
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