L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor

Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):4096-100. doi: 10.1073/pnas.91.9.4096.

Abstract

To date, numerous inhibitors of the human immunodeficiency virus type 1 protease have been reported, but few have been studied extensively in humans, primarily as a consequence of poor oral bioavailability in animal models. L-735,524 represents a class of human immunodeficiency virus type 1 protease inhibitors, termed hydroxyaminopentane amides, that incorporate a basic amine into the hydroxyethylene inhibitor backbone. L-735,524 is a potent inhibitor of virus replication in cell culture and inhibits the protease-mediated cleavage of the viral precursor polyproteins that results in the production of noninfectious progeny viral particles. The compound is effective against viruses resistant to reverse transcriptase inhibitors and is synergistically active when used in combination with reverse transcriptase inhibitors. Most importantly, L-735,524 exhibits good oral bioavailability and plasma pharmacokinetic profiles in two species of laboratory animals by using clinically acceptable formulations. Accordingly, the compound was selected for evaluation of safety and pharmacokinetic studies in humans.

MeSH terms

  • Administration, Oral
  • Animals
  • Antiviral Agents / administration & dosage*
  • Antiviral Agents / pharmacokinetics
  • Biological Availability
  • Blood Proteins / metabolism
  • Cell Line
  • Dogs
  • HIV Infections / drug therapy*
  • HIV Protease Inhibitors* / administration & dosage
  • HIV Protease Inhibitors* / pharmacokinetics
  • Humans
  • In Vitro Techniques
  • Indinavir
  • Macaca mulatta
  • Metabolic Clearance Rate
  • Pyridines / pharmacokinetics*
  • Rats
  • Virion / metabolism

Substances

  • Antiviral Agents
  • Blood Proteins
  • HIV Protease Inhibitors
  • Pyridines
  • Indinavir