The design and synthesis of novel, potent and orally bioavailable N-aryl piperazine-1-carboxamide CCR2 antagonists with very high hERG selectivity

Bioorg Med Chem Lett. 2012 Jun 15;22(12):3895-9. doi: 10.1016/j.bmcl.2012.04.118. Epub 2012 May 2.

Abstract

A novel N-aryl piperazine-1-carboxamide series of human CCR2 chemokine receptor antagonists was discovered. Early analogues were potent at CCR2 but also inhibited the hERG cardiac ion channel. Structural modifications which decreased lipophilicity and basicity resulted in the identification of a sub-series with an improved margin over hERG. The pharmacological and pharmacokinetic properties of the lead compound from this series, N-(3,4-dichlorophenyl)-4-[(2R)-4-isopropylpiperazine-2-carbonyl]piperazine-1-carboxamide, are described.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemical synthesis*
  • Anti-Inflammatory Agents / pharmacokinetics
  • Anti-Inflammatory Agents / pharmacology
  • Calcium / metabolism
  • Dogs
  • Drug Design
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Inflammation / drug therapy
  • Piperazines / chemical synthesis*
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology
  • Protein Binding
  • Rats
  • Receptors, CCR2 / antagonists & inhibitors*
  • Receptors, CCR2 / metabolism

Substances

  • Anti-Inflammatory Agents
  • CCR2 protein, human
  • Ether-A-Go-Go Potassium Channels
  • N-(3,4-dichlorophenyl)-4-((2R)-4-isopropylpiperazine-2-carbonyl)piperazine-1-carboxamide
  • Piperazines
  • Receptors, CCR2
  • Calcium