Discovery of N-propylurea 3-benzylpiperidines as selective CC chemokine receptor-3 (CCR3) antagonists

Bioorg Med Chem Lett. 2004 Apr 5;14(7):1645-9. doi: 10.1016/j.bmcl.2004.01.059.

Abstract

The discovery of novel and selective small molecule antagonists of the CC Chemokine Receptor-3 (CCR3) is presented. Simple conversion from a 4- to 3-benzylpiperidine gave improved selectivity for CCR3 over the serotonin 5HT(2A) receptor. Chiral resolution and exploration of mono- and disubstitution of the N-propylurea resulted in several 3-benzylpiperidine N-propylureas with CCR3 binding IC(50)s under 5 nM. Data from in vitro calcium mobilization and chemotaxis assays for these compounds ranged from high picomolar to low nanomolar EC(50)s and correlated well with antagonist binding IC(50)s.

MeSH terms

  • Animals
  • CHO Cells
  • Cattle
  • Cricetinae
  • Piperidines / chemistry
  • Piperidines / metabolism*
  • Protein Binding / physiology
  • Receptors, CCR3
  • Receptors, Chemokine / antagonists & inhibitors*
  • Receptors, Chemokine / metabolism*
  • Urea / analogs & derivatives*
  • Urea / chemistry
  • Urea / metabolism*

Substances

  • Piperidines
  • Receptors, CCR3
  • Receptors, Chemokine
  • propylurea
  • Urea