Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements

J Med Chem. 1999 Apr 8;42(7):1213-24. doi: 10.1021/jm9805384.

Abstract

The structure-based design, chemical synthesis, and biological evaluation of various human rhinovirus (HRV) 3C protease (3CP) inhibitors which incorporate P1 lactam moieties in lieu of an L-glutamine residue are described. These compounds are comprised of a tripeptidyl or peptidomimetic binding determinant and an ethyl propenoate Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The P1-lactam-containing inhibitors display significantly increased 3CP inhibition activity along with improved antirhinoviral properties relative to corresponding L-glutamine-derived molecules. In addition, several lactam-containing compounds exhibit excellent selectivity for HRV 3CP over several other serine and cysteine proteases and are not appreciably degraded by a variety of biological agents. One of the most potent inhibitors (AG7088, mean antirhinoviral EC90 approximately 0.10 microM, n = 46 serotypes) is shown to warrant additional preclinical development to explore its potential for use as an antirhinoviral agent.

MeSH terms

  • 3C Viral Proteases
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Cell Line
  • Crystallography, X-Ray
  • Cysteine Endopeptidases / metabolism*
  • Cysteine Proteinase Inhibitors / chemical synthesis*
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / pharmacology
  • Drug Design
  • Drug Evaluation, Preclinical
  • Glutamine / chemistry*
  • Humans
  • Isoxazoles / chemical synthesis*
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology
  • Lactams / chemical synthesis*
  • Lactams / chemistry
  • Lactams / pharmacology
  • Models, Molecular
  • Molecular Mimicry
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Phenylalanine / analogs & derivatives
  • Pyrrolidinones / chemical synthesis*
  • Pyrrolidinones / chemistry
  • Pyrrolidinones / pharmacology
  • Rhinovirus / drug effects
  • Rhinovirus / enzymology*
  • Structure-Activity Relationship
  • Valine / analogs & derivatives
  • Viral Proteins*

Substances

  • Antiviral Agents
  • Cysteine Proteinase Inhibitors
  • Isoxazoles
  • Lactams
  • Oligopeptides
  • Pyrrolidinones
  • Viral Proteins
  • Glutamine
  • Phenylalanine
  • Cysteine Endopeptidases
  • 3C Viral Proteases
  • Valine
  • rupintrivir