I. Discovery of a novel series of CXCR3 antagonists. Multiparametric optimization of N,N-disubstituted benzylamines

Bioorg Med Chem Lett. 2016 Nov 15;26(22):5418-5428. doi: 10.1016/j.bmcl.2016.10.035. Epub 2016 Oct 15.


N,N-Disubstituted benzylamine derivatives have been identified as CXCR3 antagonists. Compounds were optimized to improve affinity and selectivity, to increase metabolic stability in human and mouse liver microsomes, to increase Caco-2 permeability. Optimization was supported by monitoring physico-chemical properties using both experimental and computational means. Several compounds with double-digit nanomolar CXCR3 affinity, favorable selectivity, microsomal stability, Caco-2 permeability and human hepatocyte clearance have been identified.

Keywords: CXCR3 antagonist; Caco-2 permeability; Chemokine receptor; Inflammatory disease; Microsomal stability.

MeSH terms

  • Animals
  • Benzylamines / chemistry*
  • Benzylamines / pharmacokinetics
  • Benzylamines / pharmacology*
  • Caco-2 Cells
  • Humans
  • Mice
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Receptors, CXCR3 / antagonists & inhibitors*
  • Receptors, CXCR3 / metabolism*
  • Structure-Activity Relationship


  • Benzylamines
  • Receptors, CXCR3