Design of HIV-1 protease inhibitors active on multidrug-resistant virus

J Med Chem. 2005 Mar 24;48(6):1965-73. doi: 10.1021/jm049454n.


On the basis of structural data gathered during our ongoing HIV-1 protease inhibitors program, from which our clinical candidate TMC114 9 was selected, we have discovered new series of fused heteroaromatic sulfonamides. The further extension into the P2' region was aimed at identifying new classes of compounds with an improved broad spectrum activity and acceptable pharmacokinetic properties. Several of these compounds display an exceptional broad spectrum activity against a panel of highly cross-resistant mutants. Certain members of these series exhibit favorable pharmacokinetic profiles in rat and dog. Crystal structures and molecular modeling were used to rationalize the broad spectrum profile resulting from the extension into the P2' pocket of the HIV-1 protease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Benzoxazoles / chemical synthesis*
  • Benzoxazoles / chemistry
  • Benzoxazoles / pharmacology
  • Binding Sites
  • Calorimetry
  • Cell Line
  • Crystallography, X-Ray
  • Dogs
  • Drug Resistance, Multiple, Viral*
  • Drug Stability
  • HIV Protease Inhibitors / chemical synthesis*
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / pharmacology
  • HIV-1 / drug effects*
  • Humans
  • In Vitro Techniques
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Rats
  • Rats, Wistar
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology
  • Thermodynamics
  • Thiazoles / chemical synthesis*
  • Thiazoles / chemistry
  • Thiazoles / pharmacology


  • Benzoxazoles
  • HIV Protease Inhibitors
  • Sulfonamides
  • Thiazoles