Discovery of INCB10820/PF-4178903, a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist

Bioorg Med Chem Lett. 2011 Mar 1;21(5):1442-6. doi: 10.1016/j.bmcl.2011.01.015. Epub 2011 Jan 11.

Abstract

We report the discovery of a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist (3S,4S)-N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-3-methoxytetrahydro-2H-pyran-4-amine (19). After evaluation in 28-day toxicology studies, compound 19 (INCB10820/PF-4178903) was selected as a clinical candidate.

MeSH terms

  • Biological Availability
  • CCR5 Receptor Antagonists*
  • Caco-2 Cells
  • Drug Discovery*
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Piperazines / pharmacokinetics*
  • Piperazines / pharmacology*
  • Pyrans / chemical synthesis
  • Pyrans / chemistry
  • Pyrans / pharmacokinetics*
  • Pyrans / pharmacology*
  • Receptors, CCR2 / antagonists & inhibitors*

Substances

  • CCR2 protein, human
  • CCR5 Receptor Antagonists
  • N-(3-isopropyl-3-((4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)carbonyl)cyclopentyl)-3-methoxytetrahydro-2H-pyran-4-amine
  • Piperazines
  • Pyrans
  • Receptors, CCR2