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    Discovery of Small Molecule CXCR4 Antagonists
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    Department of Chemistry and Department of Hematology/Oncology, Winship Cancer Institute, and Department of Radiology, Emory University, Atlanta, Georgia 30322
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2007, 50, 23, 5655–5664
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    https://doi.org/10.1021/jm070679i
    Published October 24, 2007
    Copyright © 2007 American Chemical Society
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    Abstract

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    In light of a proposed molecular mechanism for the C-X-C chemokine receptor type 4 (CXCR4) antagonist 1 (AMD3100), a template with the general structure 2 was designed, and 15 was identified as a lead by means of an affinity binding assay against the ligand-mimicking CXCR4 antagonist 3 (TN14003). Following a structure−activity profile around 15, the design and synthesis of a series of novel small molecular CXCR4 antagonists led to the discovery of 32 (WZ811). The compound shows subnanomolar potency (EC50 = 0.3 nM) in an affinity binding assay. In addition, when subjected to in vitro functional evaluation, 32 efficiently inhibits CXCR4/stromal cell-derived factor-1 (SDF-1)-mediated modulation of cyclic adenosine monophophate (cAMP) levels (EC50 = 1.2 nM) and SDF-1 induced Matrigel invasion (EC50 = 5.2 nM). Molecular field topology analysis (MFTA), a 2D quantitative structure−activity relationship (QSAR) approach based on local molecular properties (Van der Waals radii (VdW), atomic charges, and local lipophilicity), applied to the 32 series suggests structural modifications to improve potency.

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    †

     Department of Chemistry.

    ‖

     W.Z. and Z.L. contributed equally to this work.

    ‡

     Department of Hematology/Oncology.

    *

     To whom correspondence should be addressed. Dennis C. Liotta, Department of Chemistry, Emory University, 1521 Dickey Drive, Atlanta, Georgia 30322. Telephone:  404-727-6602. Fax:  404-712-8679. E-mail:  [email protected]. James P. Snyder, Department of Chemistry, Emory University, 1521 Dickey Drive, Atlanta, Georgia 30322. Telephone:  404-727-2415. Fax:  404-712-8679. E-mail:  [email protected]. Hyunsuk Shim, Winship Cancer Institute, Emory University, 1365C Clifton Road, N.E., C5008, Atlanta, Georgia 30322. Telephone:  404-778-4564. Fax:  404-778-5550. E-mail:  [email protected].

    §

     Department of Radiology.

    Abbreviations:  CXCR4, C-X-C chemokine receptor type 4; SDF-1, stromal-derived factor-1; cAMP, cyclic adenosine monophosphate; AIDS, acquired immune deficiency syndrome; HIV, human immunodeficiency virus; EC, effective concentrations; MFTA, molecular field topology analysis; PLS, Partial Least Squares; QSARs, quantitative structure−activity relationships; TR-FRET, time resolved-fluorescence resonance energy transfer; TLC, thin layer chromatography; H&E, hematoxylin and eosin.

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    Figures from the competitive binding assay, additional synthetic procedures, and tables of the elemental analyses and the MFTA analysis. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cite this: J. Med. Chem. 2007, 50, 23, 5655–5664
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    Published October 24, 2007
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