Discovery and structure-activity relationships of urea derivatives as potent and novel CCR3 antagonists

Bioorg Med Chem Lett. 2012 Aug 1;22(15):4951-4. doi: 10.1016/j.bmcl.2012.06.042. Epub 2012 Jun 20.

Abstract

The synthesis and structure-activity relationships of ureas as CCR3 antagonists are described. Optimization starting with lead compound 2 (IC(50)=190 nM) derived from initial screening hit compound 1 (IC(50)=600 nM) led to the identification of (S)-N-((1R,3S,5S)-8-((6-fluoronaphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(2-nitrophenyl)pyrrolidine-1,2-dicarboxamide 27 (IC(50)=4.9 nM) as a potent CCR3 antagonist.

MeSH terms

  • Drug Evaluation, Preclinical
  • Humans
  • Naphthalenes / chemical synthesis
  • Naphthalenes / chemistry
  • Naphthalenes / metabolism
  • Proline / chemistry
  • Protein Binding
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry
  • Pyrrolidines / metabolism
  • Receptors, CCR3 / antagonists & inhibitors*
  • Receptors, CCR3 / metabolism
  • Structure-Activity Relationship
  • Urea / analogs & derivatives*
  • Urea / chemical synthesis
  • Urea / metabolism

Substances

  • (S)-N-((1R,3S,5S)-8-((6-fluoronaphthalen-2-yl)methyl)-8-azabicyclo(3.2.1)octan-3-yl)-N-(2-nitrophenyl)pyrrolidine-1,2-dicarboxamide
  • Naphthalenes
  • Pyrrolidines
  • Receptors, CCR3
  • Urea
  • Proline