Viracept (nelfinavir mesylate, AG1343): a potent, orally bioavailable inhibitor of HIV-1 protease

J Med Chem. 1997 Nov 21;40(24):3979-85. doi: 10.1021/jm9704098.

Abstract

Using a combination of iterative structure-based design and an analysis of oral pharmacokinetics and antiviral activity, AG1343 (Viracept, nelfinavir mesylate), a nonpeptidic inhibitor of HIV-1 protease, was identified. AG1343 is a potent enzyme inhibitor (Ki = 2 nM) and antiviral agent (HIV-1 ED50 = 14 nM). An X-ray cocrystal structure of the enzyme-AG1343 complex reveals how the novel thiophenyl ether and phenol-amide substituents of the inhibitor interact with the S1 and S2 subsites of HIV-1 protease, respectively. In vivo studies indicate that AG1343 is well absorbed orally in a variety of species and possesses favorable pharmacokinetic properties in humans. AG1343 (Viracept) has recently been approved for marketing for the treatment of AIDS.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / pharmacokinetics
  • Anti-HIV Agents / pharmacology*
  • Biological Availability
  • Callithrix
  • Dogs
  • Dose-Response Relationship, Drug
  • Female
  • HIV Protease Inhibitors / chemical synthesis*
  • HIV Protease Inhibitors / pharmacokinetics
  • HIV Protease Inhibitors / pharmacology*
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • Macaca fascicularis
  • Male
  • Nelfinavir / chemical synthesis*
  • Nelfinavir / pharmacokinetics
  • Nelfinavir / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • Anti-HIV Agents
  • HIV Protease Inhibitors
  • Nelfinavir