Structural optimization of aminopyrimidine-based CXCR4 antagonists

Eur J Med Chem. 2020 Feb 1:187:111914. doi: 10.1016/j.ejmech.2019.111914. Epub 2019 Nov 26.

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.

Keywords: Antagonist; CXCR4; Chemokine; GPCR; Structural optimization.

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Receptors, CXCR4 / antagonists & inhibitors*
  • Receptors, CXCR4 / metabolism
  • Structure-Activity Relationship

Substances

  • CXCR4 protein, human
  • Pyrimidines
  • Receptors, CXCR4
  • 2-aminopyrimidine