Discovery of Small Molecule CXCR4 Antagonists

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.