Structure activity relationships of fused bicyclic and urea derivatives of spirocyclic compounds as potent CCR1 antagonists

Bioorg Med Chem Lett. 2014 Jan 1;24(1):108-12. doi: 10.1016/j.bmcl.2013.11.062. Epub 2013 Dec 4.

Abstract

A series of fused bicyclic and urea derivatives of spirocyclic compounds were designed, synthesised and evaluated in vitro as potent CCR1 antagonists. In particular, 4 (7nM), 44 (1.3nM), 48 (0.89nM) and 50 (0.63nM) were the most potent hCCR1 antagonists in this series of compounds. Moreover, some of these substances demonstrated good rodent cross-over, especially 46 which exhibited very high rat CCR1 binding affinity with an IC50 value of 16nM.

Keywords: Antagonists; CCR1; Chemokines; Receptor; Spirocyclic.

MeSH terms

  • Animals
  • Bridged Bicyclo Compounds / chemistry*
  • Dose-Response Relationship, Drug
  • Molecular Structure
  • Rats
  • Receptors, CCR1 / antagonists & inhibitors*
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship
  • Urea / analogs & derivatives
  • Urea / chemistry*

Substances

  • Bridged Bicyclo Compounds
  • CCR1 protein, human
  • Receptors, CCR1
  • Spiro Compounds
  • Urea