Discovery of ((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone, PF-4254196, a CCR2 antagonist with an improved cardiovascular profile

Bioorg Med Chem Lett. 2011 May 1;21(9):2626-30. doi: 10.1016/j.bmcl.2011.01.034. Epub 2011 Jan 15.

Abstract

We describe the systematic optimization, focused on the improvement of CV-TI, of a series of CCR2 antagonists. This work resulted in the identification of 10 (((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone) which possessed a low projected human dose 35-45mg BID and a CV-TI=3800-fold.

MeSH terms

  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacokinetics
  • Anti-Inflammatory Agents / pharmacology*
  • Biological Assay
  • Humans
  • Inhibitory Concentration 50
  • Microsomes / drug effects
  • Microsomes / metabolism
  • Models, Molecular*
  • Molecular Structure
  • Piperazines / chemistry*
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology*
  • Protein Binding / drug effects
  • Pyridazines / chemistry*
  • Pyridazines / pharmacokinetics
  • Pyridazines / pharmacology*
  • Receptors, CCR2 / agonists*
  • Receptors, CCR2 / blood
  • Structure-Activity Relationship

Substances

  • ((1-isopropyl-3-(3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone)
  • Anti-Inflammatory Agents
  • Piperazines
  • Pyridazines
  • Receptors, CCR2