The important roles of the CXCL12/CXCR4 axis in numerous pathogenic pathways involving HIV infection and cancer metastasis make the CXCR4 receptor an attractive target for the development of therapeutic agents. Through scaffold hybridization of a few known CXCR4 antagonists, a series of novel aminopyrimidine derivatives was developed. Compound 3 from this new scaffold demonstrates excellent binding affinity with CXCR4 receptor (IC₅₀ = 54 nM) and inhibits CXCL12 induced cytosolic calcium increase (IC₅₀ = 2.3 nM). Furthermore, compound 3 possesses good physicochemical properties (MW 353, clogP 2.0, PSA 48, pKa 6.7) and exhibits minimal hERG and CYP isozyme (e.g. 3A4, 2D6) inhibition. Collectively, these results strongly support further optimization of this novel scaffold to develop better CXCR4 antagonists.

CXCL12 / CXCR4轴在涉及HIV感染和癌症转移的众多致病途径中的重要作用使CXCR4受体成为治疗剂开发的有吸引力的靶标。通过几种已知的CXCR4拮抗剂的支架杂交，开发了一系列新型的氨基嘧啶衍生物。来自这种新支架的化合物3表现出与CXCR4受体的优异结合亲和力（IC ₅₀  = 54 nM），并抑制CXCL12诱导的胞质钙增加（IC ₅₀  = 2.3 nM）。此外，化合物3具有良好的理化特性（MW 353，clogP 2.0，PSA 48，pKa 6.7），并且对hERG和CYP同工酶（例如3A4、2D6）的抑制作用最小。总的来说，这些结果有力地支持了该新型支架的进一步优化以开发更好的CXCR4拮抗剂。