5,6-Dihydropyran-2-ones possessing various sulfonyl functionalities: potent nonpeptidic inhibitors of HIV protease

J Med Chem. 2000 Mar 9;43(5):843-58. doi: 10.1021/jm990281p.

Abstract

On the basis of previous SAR findings and molecular modeling studies, a series of compounds were synthesized which possessed various sulfonyl moieties substituted at the 4-position of the C-3 phenyl ring substituent of the dihydropyran-2-one ring system. The sulfonyl substituents were added in an attempt to fill the additional S(3)' pocket and thereby produce increasingly potent inhibitors of the target enzyme. Racemic and enantiomerically resolved varieties of selected compounds were synthesized. All analogues in the study displayed decent binding affinity to HIV protease, and several compounds were shown to possess very good antiviral efficacy and safety margins. X-ray crystallographic structures confirmed that the sulfonamide and sulfonate moieties were filling the S(3)' pocket of the enzyme. However, the additional substituent did not provide improved enzymatic inhibitory or antiviral activity as compared to the resolved unsubstituted aniline. The addition of the sulfonyl moiety substitution does not appear to provide favorable pharamacokinectic parameters. Selected inhibitors were tested for antiviral activity in clinical isolates and exhibited similar antiviral activity against all of the HIV-1 strains tested as they did against the wild-type HIV-1. In addition, the inhibitors exhibited good antiviral efficacies against HIV-1 strains that displayed resistance to the currently marketed protease inhibitors.

MeSH terms

  • Animals
  • Arylsulfonates / chemical synthesis*
  • Arylsulfonates / chemistry
  • Arylsulfonates / pharmacokinetics
  • Arylsulfonates / pharmacology
  • Biological Availability
  • Cell Line
  • Crystallography, X-Ray
  • Cytochrome P-450 Enzyme Inhibitors
  • HIV Protease Inhibitors / chemical synthesis*
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / pharmacokinetics
  • HIV Protease Inhibitors / pharmacology
  • HIV-1 / drug effects
  • HIV-1 / isolation & purification
  • Humans
  • Lymphocytes / drug effects
  • Lymphocytes / virology
  • Mice
  • Models, Molecular
  • Pyrans / chemical synthesis*
  • Pyrans / chemistry
  • Pyrans / pharmacokinetics
  • Pyrans / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology

Substances

  • Arylsulfonates
  • Cytochrome P-450 Enzyme Inhibitors
  • HIV Protease Inhibitors
  • Pyrans
  • Sulfonamides