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

  1. Author:
    Boyer, F. E.
    Prasad, J.
    Domagala, J. M.
    Ellsworth, E. L.
    Gajda, C.
    Hagen, S. E.
    Markoski, L. J.
    Tait, B. D.
    Lunney, E. A.
    Palovsky, A.
    Ferguson, D.
    Graham, N.
    Holler, T.
    Hupe, D.
    Nouhan, C.
    Tummino, P. J.
    Urumov, A.
    Zeikus, E.
    Zeikus, G.
    Gracheck, S. J.
    Sanders, J. M.
    VanderRoest, S.
    Brodfuehrer, J.
    Iyer, K.
    Sinz, M.

  2. Author Address

    Boyer FE Parke Davis Pharmaceut Res, Dept Chem 2800 Plymouth Rd Ann Arbor, MI 48105 USA Parke Davis Pharmaceut Res, Dept Chem Ann Arbor, MI 48105 USA Parke Davis Pharmaceut Res, Dept Biochem Ann Arbor, MI 48105 USA Parke Davis Pharmaceut Res, Dept Infect Dis Ann Arbor, MI 48105 USA Parke Davis Pharmaceut Res, Dept PDM Ann Arbor, MI 48105 USA NCI, Frederick Canc Res & Dev Ctr, Struct Biochem Program, PRI Dyncorp Frederick, MD 21702 USA
    1. Year: 2000
  2. Journal: Journal of Medicinal Chemistry
    1. 43
    2. 5
    3. Pages: 843-858
  4. Type of Article: Article
  1. 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 S-3' 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. [References: 31]

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