3102
D. Kim et al. / Bioorg. Med. Chem. Lett. 11 (2001) 3099–3102
antiviral activity may be possible by further modification
around the hydantoin and tryptophan areas, the origin
of this discordant result is still under investigation.
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Compounds 27–29 and 31–34 were all found to be
selective CCR5 antagonists versus other chemokine
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Mills, S. G.; MacCoss, M.; Malkowitz, L.; Springer, M. S.;
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Gould, S. L.; DeMartino, J. A.; Siciliano, S. J.; Carella, A.;
Carver, G.; Holmes, K.; Danzeisen, R.; Hazuda, D.; Kessler,
J.; Lineberger, J.; Miller, M.; Schleif, W. A.; Emini, E. A.
Bioorg. Med. Chem. Lett. 2001, 11, 265. (c) Finke, P. E.;
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kowitz, L.; Springer, M. S.; Gould, S. L.; DeMartino, J. A.;
Carella, A.; Carver, G.; Holmes, K.; Schleif, W. A.; Danzei-
sen, R.; Hazuda, D.; Kessler, J.; Lineberger, J.; Miller, M.;
Emini, E. A. Bioorg. Med. Chem. Lett. 2001, 11, 2469. (d)
Finke, P. E.; Oates, B.; Meurer, L. C.; Mills, S. G.; . MacCoss,
M.; Malkowitz, L.; Springer, M. S.; Gould, S. L.; DeMartino,
J. A.; Carella, A.; Carver, G.; Holmes, K.; Schleif, W. A.;
Danzeisen, R.; Hazuda, D.; Kessler, J.; Lineberger, J.; Miller,
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Caldwell, C. G.; Chen, P.; Donnelly, K. F.; Finke, P. E.;
Shankaran, K.; Meurer, L. C.; Oates, B.; MacCoss, M.; Mills,
S. G.; Malkowitz, L.; Springer, M. S.; Gould, S. L.; DeMar-
tino, J. A.; Carella, A.; Carver, G.; Holmes, K.; Schleif, W. A.;
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M.; Emini, E. A. Abstracts of Papers, 219th National Meeting
of the American Chemical Society, San Francisco, CA,;
American Chemical Society: Washington, DC, 2000; Abstract
MEDI 120 (manuscript in preparation for submission to
Bioorg. Med. Chem. Lett.).
In summary, starting with lead I as a design template, a
series of hydantoin-based CCR5 receptor antagonists was
synthesized and evaluated for their binding potency as
well as antiviral activity. Replacement of the sulfonamide
with a hydantoin moiety was possible. Aromatic amino
acid derivatives were found to be active in the binding
assay with the d-tryptophan derivative 28 being the
most potent compound. When coupled with carba-
mates, benzylic methyl, or 3-chloro, antiviral activity
increased in our series (Table 3). This suggests that efficient
inhibition of HIV-1 replication may be possible by further
modification of potent hydantoin-based CCR5 antago-
nists, blocking entry of M-tropic HIV viral strains into
the host cells effectively.
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