II. Discovery of a novel series of CXCR3 antagonists with a beta amino acid core

Bioorg Med Chem Lett. 2016 Nov 15;26(22):5429-5437. doi: 10.1016/j.bmcl.2016.10.038. Epub 2016 Oct 15.

Abstract

A new series of beta amino acids, which act as CXCR3 antagonists, has been identified. The formerly optimized N,N-disubstituted benzylamine derivatives with carboxylic acid function on the N-atom was used as starting point and compounds with carboxyl function not attached to the N-atom were investigated. Affinity, metabolic stability in human and mouse liver microsomes and Caco-2 permeability were optimized. Compounds with double-digit nanomolar CXCR3 affinity, favourable microsomal stability and Caco-2 permeability have been identified.

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

MeSH terms

  • Amino Acids / chemistry*
  • Amino Acids / pharmacokinetics
  • Amino Acids / pharmacology*
  • Animals
  • Benzylamines / chemistry*
  • Benzylamines / pharmacokinetics
  • Benzylamines / pharmacology*
  • Caco-2 Cells
  • Drug Discovery
  • Humans
  • Mice
  • Microsomes, Liver / metabolism
  • Receptors, CXCR3 / antagonists & inhibitors*
  • Receptors, CXCR3 / metabolism

Substances

  • Amino Acids
  • Benzylamines
  • CXCR3 protein, human
  • Receptors, CXCR3