Selection of a respiratory syncytial virus fusion inhibitor clinical candidate, part 1: improving the pharmacokinetic profile using the structure-property relationship

J Med Chem. 2007 Sep 20;50(19):4572-84. doi: 10.1021/jm070143x. Epub 2007 Aug 28.


We previously reported the discovery of substituted benzimidazole fusion inhibitors with nanomolar activity against respiratory syncytial virus (Andries, K.; et al. Antiviral Res. 2003, 60, 209-219). A lead compound of the series was selected for preclinical evaluation. This drug candidate, JNJ-2408068 (formerly R170591, 1), showed long tissue retention times in several species (rat, dog, and monkey), creating cause for concern. We herein describe the optimization program to develop compounds with improved properties in terms of tissue retention. We have identified the aminoethyl-piperidine moiety as being responsible for the long tissue retention time of 1. We have investigated the replacement or the modification of this group, and we suggest that the pKa of this part of the molecules influences both the antiviral activity and the pharmacokinetic profile. We were able to identify new respiratory syncytial virus inhibitors with shorter half-lives in lung tissue.

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / pharmacokinetics
  • Benzimidazoles / pharmacology
  • HeLa Cells
  • Humans
  • Kidney / metabolism
  • Liver / metabolism
  • Lung / metabolism
  • Male
  • Piperidines / chemical synthesis*
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Respiratory Syncytial Viruses / drug effects*
  • Structure-Activity Relationship
  • Tissue Distribution
  • Viral Fusion Proteins / antagonists & inhibitors*


  • 2((2-((1-(2-aminoethyl)-4-piperidinyl)amino)-4-methyl-1H-benzimidazol-1-yl)methyl)-6-methyl-3-pyridinol
  • Antiviral Agents
  • Benzimidazoles
  • Piperidines
  • Pyridines
  • Viral Fusion Proteins