Design and synthesis of ethyl pyrrolidine-5,5-trans-lactams as inhibitors of hepatitis C virus NS3/4A protease

Bioorg Med Chem Lett. 2002 Dec 2;12(23):3359-62. doi: 10.1016/s0960-894x(02)00789-8.

Abstract

Using a pyrrolidine-5,5-trans-lactam template, we have designed small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. Compound 11a, with an alpha-ethyl P1 substituent and a Boc-valine substituent at the pyrrolidine nitrogen, has an IC(50)=30 microM.

MeSH terms

  • Amino Acid Sequence
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / metabolism
  • Drug Design
  • Hepacivirus / drug effects
  • Hepacivirus / enzymology*
  • Humans
  • Inhibitory Concentration 50
  • Intracellular Signaling Peptides and Proteins
  • Lactams / chemical synthesis
  • Lactams / chemistry*
  • Lactams / pharmacology*
  • Microbial Sensitivity Tests
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry*
  • Serine Proteinase Inhibitors / chemical synthesis*
  • Serine Proteinase Inhibitors / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / metabolism

Substances

  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Lactams
  • NS3 protein, hepatitis C virus
  • NS4A cofactor peptide, Hepatitis C virus
  • Pyrrolidines
  • Serine Proteinase Inhibitors
  • Viral Nonstructural Proteins
  • Viral Proteins