Rodent selectivity of piperidine-4-yl-1H-indoles, a series of CC chemokine receptor-3 (CCR3) antagonists: insights from a receptor model

Bioorg Med Chem Lett. 2015 Jan 15;25(2):229-35. doi: 10.1016/j.bmcl.2014.11.063. Epub 2014 Nov 27.

Abstract

Rodent selectivity data of piperidine-4-yl-1H-indoles, a series of CC chemokine receptor-3 (CCR3) antagonists, are presented and discussed as part of an overall optimization effort within this lead compound class. Although attachment of an acidic moiety to the 1-position of the indole led to an overall balanced in vitro profile, in particular reducing inhibition of the hERG channel, potency on the rat and mouse receptor worsened. These findings could be rationalized in the context of a CCR3 homology model.

Keywords: CCR3; Chemokine; Piperidine-4-yl-1H-indoles; Receptor model; Rodent selectivity; hERG.

MeSH terms

  • Animals
  • Humans
  • Indoles / chemistry*
  • Indoles / metabolism
  • Indoles / pharmacology
  • Mice
  • Models, Molecular*
  • Piperidines / chemistry*
  • Piperidines / metabolism
  • Piperidines / pharmacology
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Rats
  • Receptors, CCR3 / antagonists & inhibitors*
  • Receptors, CCR3 / metabolism
  • Species Specificity

Substances

  • Indoles
  • Piperidines
  • Receptors, CCR3
  • piperidine
  • indole