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- W3044906489 endingPage "112537" @default.
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- W3044906489 abstract "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 CXLC12/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." @default.
- W3044906489 created "2020-07-29" @default.
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- W3044906489 date "2020-11-01" @default.
- W3044906489 modified "2023-10-01" @default.
- W3044906489 title "Design, synthesis, and evaluation of pyrrolidine based CXCR4 antagonists with in vivo anti-tumor metastatic activity" @default.
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- W3044906489 doi "https://doi.org/10.1016/j.ejmech.2020.112537" @default.
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