L-735,524: the design of a potent and orally bioavailable HIV protease inhibitor

J Med Chem. 1994 Oct 14;37(21):3443-51. doi: 10.1021/jm00047a001.


A series of HIV protease inhibitors possessing a hydroxylaminepentanamide transition state isostere have been developed. Incorporation of a basic amine into the backbone of the L-685,434 (2) series provided antiviral potency combined with a highly improved pharmacokinetic profile in animal models. Guided by molecular modeling and an X-ray crystal structure of the inhibited enzyme complex, we were able to design L-735,524. This compound is potent and competitively inhibits HIV-1 PR and HIV-2 PR with Ki values of 0.52 and 3.3 nM, respectively. It also stops the spread of the HIV-1IIIb-infected MT4 lymphoid cells at concentrations of 25-50 nM. To date, numerous HIV-PR inhibitors have been reported, but few have been studied in humans because they lack acceptable oral bioavailability. L-735,524 is orally bioavailable in three animals models, using clinically acceptable formulations, and is currently in phase II human clinical trials.

MeSH terms

  • Animals
  • Binding, Competitive
  • Biological Availability
  • Cell Line
  • Crystallography, X-Ray
  • Dogs
  • Drug Design
  • HIV Protease / metabolism
  • HIV Protease Inhibitors / chemical synthesis*
  • HIV Protease Inhibitors / pharmacokinetics
  • HIV Protease Inhibitors / pharmacology
  • HIV-1 / drug effects
  • HIV-1 / enzymology
  • HIV-1 / growth & development
  • HIV-2 / enzymology
  • Humans
  • Indinavir
  • Models, Molecular
  • Molecular Structure
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology
  • Rats
  • T-Lymphocytes / virology


  • HIV Protease Inhibitors
  • Pyridines
  • Indinavir
  • HIV Protease