SAR studies on a series of N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamides: potent inhibitors of the polymerase enzyme (NS5B) of the hepatitis C virus

Bioorg Med Chem Lett. 2011 May 15;21(10):3142-7. doi: 10.1016/j.bmcl.2011.03.008. Epub 2011 Mar 6.

Abstract

Described herein is the initial optimization of (+/-) N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamide (1), a hit discovered in a high throughput screen run against the NS5B polymerase enzyme of the hepatitis C virus. This effort resulted in the identification of (S)-N-sec-butyl-6-((R)-3-(4-(trifluoromethoxy)benzylcarbamoyl)-4-(4-(trifluoromethoxy)phenylsulfonyl)piperazin-1-yl)pyridazine-3-carboxamide (2), that displayed potent replicon activities against HCV genotypes 1b and 1a (EC(50) 1b/1a=7/89 nM).

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Catalytic Domain
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Hepacivirus* / enzymology
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Piperazine
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

  • Amides
  • Enzyme Inhibitors
  • Piperazines
  • Viral Nonstructural Proteins
  • Piperazine
  • NS-5 protein, hepatitis C virus