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Design, synthesis, and evaluation of pyrrolidine based CXCR4 antagonists with in vivo anti-tumor metastatic activity.

Abstract
The chemokine receptor CXCR4 has been proposed as a drug target based on its important functions in HIV infection, inflammation/autoimmune diseases and cancer metastasis. Herein we report the design, synthesis and evaluation of novel CXCR4 antagonists based on a pyrrolidine scaffold. The structural exploration/optimization identified numerous potent CXCR4 antagonists, represented by compound 46, which displayed potent binding affinity to CXCR4 receptor (IC50 = 79 nM competitively displacing fluorescent 12G5 antibody) and inhibited CXCL12 induced cytosolic calcium flux (IC50 = 0.25 nM). Moreover, in a transwell invasion assay, compound 46 significantly mitigated CXCL12/CXCR4 mediated cell migration. Compound 46 exhibited good physicochemical properties (MW 367, logD7.4 1.12, pKa 8.2) and excellent in vitro safety profiles (e.g., hERG patch clamp IC50 > 30 μM and minimal CYP isozyme inhibition). Importantly, 46 displayed much improved metabolic stability in human and rat liver microsomes. Lastly, 46 demonstrated marked efficacy in a cancer metastasis model in mice. These results strongly support 46 as a prototypical lead for the development of promising CXCR4 antagonists as clinical candidates.
AuthorsZhanhui Li, Xu Wang, Yu Lin, Yujie Wang, Shuwei Wu, Kaijiang Xia, Chen Xu, Haikuo Ma, Jiyue Zheng, Lusong Luo, Fang Zhu, Sudan He, Xiaohu Zhang
JournalEuropean journal of medicinal chemistry (Eur J Med Chem) Vol. 205 Pg. 112537 (Nov 01 2020) ISSN: 1768-3254 [Electronic] France
PMID32768738 (Publication Type: Journal Article)
CopyrightCopyright © 2020 Elsevier Masson SAS. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • CXCR4 protein, human
  • Pyrrolidines
  • Receptors, CXCR4
  • pyrrolidine
  • Calcium
Topics
  • Animals
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Calcium (metabolism)
  • Cell Line, Tumor
  • Chemistry Techniques, Synthetic
  • Cytosol (drug effects, metabolism)
  • Drug Design
  • Humans
  • Mice
  • Neoplasm Metastasis
  • Pyrrolidines (chemical synthesis, chemistry, pharmacology)
  • Rats
  • Receptors, CXCR4 (antagonists & inhibitors)

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