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 journalArticle

23 Citations (Scopus)

Abstract

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
Volume7
Issue number12
DOIs
StatePublished - Dec 1 1999

Fingerprint

HIV Protease Inhibitors
Antiviral Agents
HIV
Peptidomimetics
Pyrans
Cytochrome P-450 CYP3A
Pharmacokinetics
Hydroxyl Radical
Biological Availability
Half-Life
Toxicity
Substitution reactions
Therapeutics
Crystal structure
X-Rays
Availability
X rays
Enzymes
PD 178390
Lead

Keywords

  • 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

Cite this

Vara Prasad, J. V. N., Boyer, F. E., Domagala, J. M., Ellsworth, E. L., Gajda, C., Hamilton, H. W., ... Erickson, J. W. (1999). Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: A lead HIV protease inhibitor. Bioorganic and Medicinal Chemistry, 7(12), 2775-2800. https://doi.org/10.1016/S0968-0896(99)00215-1

Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390 : A lead HIV protease inhibitor. / Vara Prasad, J. V.N.; Boyer, Frederick E.; Domagala, John M.; Ellsworth, Edmund L.; Gajda, Christopher; Hamilton, Harriet W.; Hagen, Susan E.; Markoski, Larry J.; Steinbaugh, Bruce A.; Tait, Bradley D.; Humblet, Christine; Lunney, Elizabeth A.; Pavlovsky, Alexander; Rubin, John R.; Ferguson, Donna; Graham, Neil; Holler, Tod; Hupe, Donald; Nouhan, Carolyn; Tummino, Peter J.; Urumov, A.; Zeikus, Eric; Zeikus, Greg; Gracheck, Stephen J.; Saunders, James M.; Vanderroest, Steven; Brodfuehrer, Joanne; Iyer, K.; Sinz, M.; Gulnik, Sergei V.; Erickson, John W.

In: Bioorganic and Medicinal Chemistry, Vol. 7, No. 12, 01.12.1999, p. 2775-2800.

Research output: Contribution to journalArticle

Vara Prasad, JVN, Boyer, FE, Domagala, JM, Ellsworth, EL, Gajda, C, Hamilton, HW, Hagen, SE, Markoski, LJ, Steinbaugh, BA, Tait, BD, Humblet, C, Lunney, EA, Pavlovsky, A, Rubin, JR, Ferguson, D, Graham, N, Holler, T, Hupe, D, Nouhan, C, Tummino, PJ, Urumov, A, Zeikus, E, Zeikus, G, Gracheck, SJ, Saunders, JM, Vanderroest, S, Brodfuehrer, J, Iyer, K, Sinz, M, Gulnik, SV & Erickson, JW 1999, 'Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: A lead HIV protease inhibitor', Bioorganic and Medicinal Chemistry, vol. 7, no. 12, pp. 2775-2800. https://doi.org/10.1016/S0968-0896(99)00215-1
Vara Prasad, J. V.N. ; Boyer, Frederick E. ; Domagala, John M. ; Ellsworth, Edmund L. ; Gajda, Christopher ; Hamilton, Harriet W. ; Hagen, Susan E. ; Markoski, Larry J. ; Steinbaugh, Bruce A. ; Tait, Bradley D. ; Humblet, Christine ; Lunney, Elizabeth A. ; Pavlovsky, Alexander ; Rubin, John R. ; Ferguson, Donna ; Graham, Neil ; Holler, Tod ; Hupe, Donald ; Nouhan, Carolyn ; Tummino, Peter J. ; Urumov, A. ; Zeikus, Eric ; Zeikus, Greg ; Gracheck, Stephen J. ; Saunders, James M. ; Vanderroest, Steven ; Brodfuehrer, Joanne ; Iyer, K. ; Sinz, M. ; Gulnik, Sergei V. ; Erickson, John W. / Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390 : A lead HIV protease inhibitor. In: Bioorganic and Medicinal Chemistry. 1999 ; Vol. 7, No. 12. pp. 2775-2800.
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abstract = "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.",
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T1 - Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390

T2 - A lead HIV protease inhibitor

AU - Vara Prasad, J. V.N.

AU - Boyer, Frederick E.

AU - Domagala, John M.

AU - Ellsworth, Edmund L.

AU - Gajda, Christopher

AU - Hamilton, Harriet W.

AU - Hagen, Susan E.

AU - Markoski, Larry J.

AU - Steinbaugh, Bruce A.

AU - Tait, Bradley D.

AU - Humblet, Christine

AU - Lunney, Elizabeth A.

AU - Pavlovsky, Alexander

AU - Rubin, John R.

AU - Ferguson, Donna

AU - Graham, Neil

AU - Holler, Tod

AU - Hupe, Donald

AU - Nouhan, Carolyn

AU - Tummino, Peter J.

AU - Urumov, A.

AU - Zeikus, Eric

AU - Zeikus, Greg

AU - Gracheck, Stephen J.

AU - Saunders, James M.

AU - Vanderroest, Steven

AU - Brodfuehrer, Joanne

AU - Iyer, K.

AU - Sinz, M.

AU - Gulnik, Sergei V.

AU - Erickson, John W.

PY - 1999/12/1

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N2 - 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.

AB - 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.

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KW - Antivirals

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