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.
S W Kaldor  1 ,  V J Kalish ,  J F Davies 2nd ,  B V Shetty ,  J E Fritz ,  K Appelt ,  J A Burgess ,  K M Campanale ,  N Y Chirgadze ,  D K Clawson ,  B A Dressman ,  S D Hatch ,  D A Khalil ,  M B Kosa ,  P P Lubbehusen ,  M A Muesing ,  A K Patick ,  S H Reich ,  K S Su ,  J H Tatlock
Affiliations
  • 1. Agouron Pharmaceuticals, Inc., San Diego, California 92121, USA.
PMID: 9397180 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.

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