Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: A lead HIV protease inhibitor

J. V.N. Vara Prasad, Frederick E. Boyer, John M. Domagala, Edmund L. Ellsworth, Christopher Gajda, Harriet W. Hamilton, Susan E. Hagen, Larry J. Markoski, Bruce A. Steinbaugh, Bradley D. Tait, Christine Humblet, Elizabeth A. Lunney, Alexander Pavlovsky, John R. Rubin, Donna Ferguson, Neil Graham, Tod Holler, Donald Hupe, Carolyn Nouhan, Peter J. TumminoA. Urumov, Eric Zeikus, Greg Zeikus, Stephen J. Gracheck, James M. Saunders, Steven Vanderroest, Joanne Brodfuehrer, K. Iyer, M. Sinz, Sergei V. Gulnik, John W. Erickson

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


With the insight generated by the availability of X-ray crystal structures of various 5,6-dihydropyran-2-ones bound to HIV PR, inhibitors possessing various alkyl groups at the 6-position of 5,6-dihydropyran-2-one ring were synthesized. The inhibitors possessing a 6-alkyl group exhibited superior antiviral activities when compared to 6-phenyl analogues. Antiviral efficacies were further improved upon introduction of a polar group (hydroxyl or amino) on the 4-position of the phenethyl moiety as well as the polar group (hydroxymethyl) on the 3-(tert-butyl-5-methyl-phenylthio) moiety. The polar substitution is also advantageous for decreasing toxicity, providing inhibitors with higher therapeutic indices. The best inhibitor among this series, (S)-6-[2-(4-aminophenyl)-ethyl]-(3-(2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (34S), exhibited an EC50 of 200 nM with a therapeutic index of >1000. More importantly, these non-peptidic inhibitors, 16S and 34S, appear to offer little cross-resistance to the currently marketed peptidomimetic PR inhibitors. The selected inhibitors tested in vitro against mutant HIV PR showed a very small increase in binding affinities relative to wild-type HIV PR. C(max) and absolute bioavailability of 34S were higher and half-life and time above EC95 were longer compared to 16S. Thus 34S, also known as PD 178390, which displays good antiviral efficacy, promising pharmacokinetic characteristics and favorable activity against mutant enzymes and CYP3A4, has been chosen for further preclinical evaluation. Copyright (C) 1999 Elsevier Science Ltd.

Original languageEnglish (US)
Pages (from-to)2775-2800
Number of pages26
JournalBioorganic and Medicinal Chemistry
Issue number12
StatePublished - Dec 1999


  • Anti-HIV agents
  • Antivirals
  • Aspartic protease inhibitors
  • HIV protease inhibitors
  • Nonpeptidic HIV protease inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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