Structural optimization of aminopyrimidine-based CXCR4 antagonists


European Journal of Medicinal Chemistry


FangZhu, Yuji Wang, Qian Du, Wenxiang Ge, Zhanhui Li, Xu Wang, Chunyan Fu, Lusong Luo, Sheng Tian, Haikuo Ma, Jiyue Zheng, Yi Zhang, Xiaotian Sun, Sudan He, Xiaohu Zhang



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 a 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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