5,6-Dihydropyran-2-ones possessing various sulfonyl functionalities: Potent nonpeptidic inhibitors of HIV protease

Frederick E. Boyer, J. V.N. Vara Prasad, John M. Domagala, Edmund L. Ellsworth, Christopher Gajda, Susan E. Hagen, Larry J. Markoski, Bradley D. Tait, Elizabeth A. Lunney, Alexander Palovsky, Donna Ferguson, Neil Graham, Tod Holler, Donald Hupe, Carolyn Nouhan, Peter J. Tummino, A. Urumov, Eric Zeikus, Greg Zeikus, Stephen J. GracheckJames M. Sanders, Steven VanderRoest, Joanne Brodfuehrer, Krishna Iyer, Michael Sinz, Sergei V. Gulnik, John W. Erickson

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

On the basis of previous SAR findings and molecular modeling studies, a series of compounds were synthesized which possessed various sulfonyl moieties substituted at the 4-position of the C-3 phenyl ring substituent of the dihydropyran-2-one ring system. The sulfonyl substituents were added in an attempt to fill the additional S3' pocket and thereby produce increasingly potent inhibitors of the target enzyme. Racemic and enantiomerically resolved varieties of selected compounds were synthesized. All analogues in the study displayed decent binding affinity to HIV protease, and several compounds were shown to possess very good antiviral efficacy and safety margins. X-ray crystallographic structures confirmed that the sulfonamide and sulfonate moieties were filling the S3' pocket of the enzyme. However, the additional substituent did not provide improved enzymatic inhibitory or antiviral activity as compared to the resolved unsubstituted aniline. The addition of the sulfonyl moiety substitution does not appear to provide favorable pharamacokinectic parameters. Selected inhibitors were tested for antiviral activity in clinical isolates and exhibited similar antiviral activity against all of the HIV-1 strains tested as they did against the wild-type HIV-1. In addition, the inhibitors exhibited good antiviral efficacies against HIV-1 strains that displayed resistance to the currently marketed protease inhibitors.

Original languageEnglish (US)
Pages (from-to)843-858
Number of pages16
JournalJournal of Medicinal Chemistry
Volume43
Issue number5
DOIs
StatePublished - Mar 9 2000

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HIV Protease Inhibitors
Antiviral Agents
HIV-1
HIV Protease
Sulfonamides
Enzyme Inhibitors
Protease Inhibitors
X-Rays
Safety
Enzymes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Boyer, F. E., Vara Prasad, J. V. N., Domagala, J. M., Ellsworth, E. L., Gajda, C., Hagen, S. E., ... Erickson, J. W. (2000). 5,6-Dihydropyran-2-ones possessing various sulfonyl functionalities: Potent nonpeptidic inhibitors of HIV protease. Journal of Medicinal Chemistry, 43(5), 843-858. https://doi.org/10.1021/jm990281p

5,6-Dihydropyran-2-ones possessing various sulfonyl functionalities : Potent nonpeptidic inhibitors of HIV protease. / Boyer, Frederick E.; Vara Prasad, J. V.N.; Domagala, John M.; Ellsworth, Edmund L.; Gajda, Christopher; Hagen, Susan E.; Markoski, Larry J.; Tait, Bradley D.; Lunney, Elizabeth A.; Palovsky, Alexander; Ferguson, Donna; Graham, Neil; Holler, Tod; Hupe, Donald; Nouhan, Carolyn; Tummino, Peter J.; Urumov, A.; Zeikus, Eric; Zeikus, Greg; Gracheck, Stephen J.; Sanders, James M.; VanderRoest, Steven; Brodfuehrer, Joanne; Iyer, Krishna; Sinz, Michael; Gulnik, Sergei V.; Erickson, John W.

In: Journal of Medicinal Chemistry, Vol. 43, No. 5, 09.03.2000, p. 843-858.

Research output: Contribution to journalArticle

Boyer, FE, Vara Prasad, JVN, Domagala, JM, Ellsworth, EL, Gajda, C, Hagen, SE, Markoski, LJ, Tait, BD, Lunney, EA, Palovsky, A, Ferguson, D, Graham, N, Holler, T, Hupe, D, Nouhan, C, Tummino, PJ, Urumov, A, Zeikus, E, Zeikus, G, Gracheck, SJ, Sanders, JM, VanderRoest, S, Brodfuehrer, J, Iyer, K, Sinz, M, Gulnik, SV & Erickson, JW 2000, '5,6-Dihydropyran-2-ones possessing various sulfonyl functionalities: Potent nonpeptidic inhibitors of HIV protease', Journal of Medicinal Chemistry, vol. 43, no. 5, pp. 843-858. https://doi.org/10.1021/jm990281p
Boyer, Frederick E. ; Vara Prasad, J. V.N. ; Domagala, John M. ; Ellsworth, Edmund L. ; Gajda, Christopher ; Hagen, Susan E. ; Markoski, Larry J. ; Tait, Bradley D. ; Lunney, Elizabeth A. ; Palovsky, Alexander ; Ferguson, Donna ; Graham, Neil ; Holler, Tod ; Hupe, Donald ; Nouhan, Carolyn ; Tummino, Peter J. ; Urumov, A. ; Zeikus, Eric ; Zeikus, Greg ; Gracheck, Stephen J. ; Sanders, James M. ; VanderRoest, Steven ; Brodfuehrer, Joanne ; Iyer, Krishna ; Sinz, Michael ; Gulnik, Sergei V. ; Erickson, John W. / 5,6-Dihydropyran-2-ones possessing various sulfonyl functionalities : Potent nonpeptidic inhibitors of HIV protease. In: Journal of Medicinal Chemistry. 2000 ; Vol. 43, No. 5. pp. 843-858.
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T2 - Potent nonpeptidic inhibitors of HIV protease

AU - Boyer, Frederick E.

AU - Vara Prasad, J. V.N.

AU - Domagala, John M.

AU - Ellsworth, Edmund L.

AU - Gajda, Christopher

AU - Hagen, Susan E.

AU - Markoski, Larry J.

AU - Tait, Bradley D.

AU - Lunney, Elizabeth A.

AU - Palovsky, Alexander

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 - Sanders, James M.

AU - VanderRoest, Steven

AU - Brodfuehrer, Joanne

AU - Iyer, Krishna

AU - Sinz, Michael

AU - Gulnik, Sergei V.

AU - Erickson, John W.

PY - 2000/3/9

Y1 - 2000/3/9

N2 - On the basis of previous SAR findings and molecular modeling studies, a series of compounds were synthesized which possessed various sulfonyl moieties substituted at the 4-position of the C-3 phenyl ring substituent of the dihydropyran-2-one ring system. The sulfonyl substituents were added in an attempt to fill the additional S3' pocket and thereby produce increasingly potent inhibitors of the target enzyme. Racemic and enantiomerically resolved varieties of selected compounds were synthesized. All analogues in the study displayed decent binding affinity to HIV protease, and several compounds were shown to possess very good antiviral efficacy and safety margins. X-ray crystallographic structures confirmed that the sulfonamide and sulfonate moieties were filling the S3' pocket of the enzyme. However, the additional substituent did not provide improved enzymatic inhibitory or antiviral activity as compared to the resolved unsubstituted aniline. The addition of the sulfonyl moiety substitution does not appear to provide favorable pharamacokinectic parameters. Selected inhibitors were tested for antiviral activity in clinical isolates and exhibited similar antiviral activity against all of the HIV-1 strains tested as they did against the wild-type HIV-1. In addition, the inhibitors exhibited good antiviral efficacies against HIV-1 strains that displayed resistance to the currently marketed protease inhibitors.

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