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  • Title: Structural optimization of aminopyrimidine-based CXCR4 antagonists.
    Author: Zhu F, Wang Y, Du Q, Ge W, Li Z, Wang X, Fu C, Luo L, Tian S, Ma H, Zheng J, Zhang Y, Sun X, He S, Zhang X.
    Journal: Eur J Med Chem; 2020 Feb 01; 187():111914. PubMed ID: 31806538.
    Abstract:
    Structural optimization of aminopyrimidine-based CXCR4 antagonists is reported. The optimization is guided by molecular docking studies based on available CXCR4-small molecule crystal complex. The optimization identifies a number of compounds with improved receptor binding affinity and functional activity exemplified by compound 23 (inhibition of APC-conjugate clone 12G5 for CXCR4 binding in a cell based assay: IC50 = 8.8 nM; inhibition of CXCL12 induced cytosolic calcium increase: IC50 = 0.02 nM). In addition, compound 23 potently inhibits CXCR4/CXLC12 mediated chemotaxis in a matrigel invasion assay. Furthermore, compound 23 exhibits good physicochemical properties (MW 367, clogP 2.1, PSA 48, pKa 7.2) and in vitro safety profiles (marginal/moderate inhibition of CYP isozymes and hERG). These results represent significant improvement over the initial hit from scaffold hybridization and suggest that compound 23 can be used as a starting point to support lead optimization.
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