3486 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19
Communications to the Editor
Bethell, R. C.; Hotham, V. J .; Cameron, J . M.; Penn, C. R.
Rational design of potent sialidase-based inhibitors of influenza
virus replication. Nature 1993, 363, 418-423.
successful identification of a new enzyme inhibitor. We
believe that this approach of analyzing ligands bound
to protein crystals has wide applicability for screening
mixtures of compounds to identify the active compound.
Due to its in vitro and in vivo activity against influenza
A and B, further studies with 8 in humans are war-
ranted, and it is currently in human clinical trials for
the management of influenza.
(7) Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H. T.; Zhang, L. J .;
Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D.
B.; Tai, C. Y.; Laver, W. G.; Stevens, R. C. Influenza neuramini-
dase inhibitors possessing a novel hydrophobic interaction in the
enzyme active site: design, synthesis, and structural analysis
of carbocyclic sialic acid analogues with potent anti-influenza
activity. J . Am. Chem. Soc. 1997, 119, 681-690.
(8) Meindl, P.; Bodo, G.; Palese, P.; Schulman, J .; Tuppy, H.
Inhibition of neuraminidase activity by derivatives of 2-deoxy-
2,3-dehydro-N-acetyl-neuraminic acid. Virology 1974, 58, 457-
463.
(9) Bossart-Whitaker, P.; Carson, M.; Babu, Y. S.; Smith, C. D.;
Laver, W. G.; Air, G. M. Three-dimensional structure of influenza
A N9 neuraminidase and its complex with inhibitor 2-deoxy-
2,3-dehydro-N-acetyl-neuraminic acid. J . Mol. Biol. 1993, 232,
1069-1083.
(10) Nohle, U.; Beau, J . M.; Schauer, R. Uptake, metabolism and
excretion of orally administered double-labeled N-glycoloyl-
neuraminic acid and single-labeled 2-deoxy-2,3-dehydro-N-
acetylneuraminic acid in mouse and rat. Eur. J . Biochem. 1982,
126, 543-548.
(11) Yamamoto, T.; Kumazawa, H.; Inami, K.; Teshima, T.; Shiba,
T. Synthesis of sialic acid isomers with inhibitory activity against
neuraminidase. Tetrahedron Lett. 1992, 33, 5791-5794.
(12) Taylor, N. R.; von Itzstein, M. Molecular modeling studies on
ligand binding to sialidase from influenza virus and the mech-
anism of catalysis. J . Med. Chem. 1994, 37, 616-624.
(13) Taylor, N. R.; Cleasby, A.; Singh, O.; Skarzynski, T.; Wonacott,
A. J .; Sollis, S. L.; Howes, P. D.; Cherry, P. C.; Bethell, R.;
Colman, P.; Varghese, J . Dihydropyrancarboxamides related to
zanamivir: A new series of inhibitors of Influenza virus siali-
dases. 2. Crystallographic and molecular modeling study of
complexes of 4-amino-4H-pyran-6-carboxamides and sialidase
from influenza virus types A and B. J . Med. Chem. 1998, 41,
798-807.
(14) Gubareva, L. V.; Schallon, D.; Hayden, F. G. Activity of the
neuraminidase inhibitor RWJ -270201 (BCX-1812) in the neur-
aminidase inhibition assays. II International Symposium on
Influenza and other Respiratory Viruses, Dec 10-12, 1999;
Abstract.
(15) Gubareva, L. V.; Kaiser, L.; Hayden, F. G. Influenza virus
neuraminidase inhibitors. Lancet 2000, 355, 827-835.
(16) Potier, M.; Mameli, L.; Belisle, M.; Dallaire, L.; Melancon, S.
B.; Fluorometric assay of neuraminidase with a sodium (4-
methylumbelliferyl-alpha-D-N-acetylneuraminate) substrate.
Anal. Biochem. 1979, 94, 287-296.
Ack n ow led gm en t. The authors thank Dr. Scott
Rowland for many helpful discussions and computer
graphics illustrations; Drs. Brent Cole and Naiming Chu
for help in X-ray diffraction data collection and process-
ing; Ms. Debbie Kellogg for assistance in animal efficacy
studies; and Dr. Tetsuo Shiba of the Protein Research
Foundation, Osaka, J apan, for providing a sample of 5
for our crystallographic studies. Finally, we also grate-
fully acknowledge the constant encouragement and
support from Drs. Claude Bennett and Charlie Bugg
throughout this project.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails about X-ray crystallographic data collection and process-
ing. This material is available free of charge via the Internet
at http://pubs.acs.org.
Refer en ces
(1) Monto, A. S.; Iacuzio, I. A.; LaMontague, J . R. Pandemic
Influenza-confronting a reemergent threat. J . Infect. Dis. 1997,
176, 51-53.
(2) Glezen, W. P. Serious morbidity and mortality associated with
influenza epidemics. Epidemiol. Rev. 1982, 4, 25-44.
(3) Hayden, F. G.; Couch, R. B. Clinical and epidemiological
importance of influenza A viruses resistant to amantadine and
rimantadine. Rev. Med. Virol. 1992, 2, 89-96.
(4) Webster, R. G.; Reay, P. A.; Laver, W. G. Protection against
lethal influenza with neuraminidase. Virology 1988, 164, 230-
237.
(5) Liu, C.; Eichelberger, M. C.; Compans, R. W.; Air, G. M.
Influenza type A virus neuraminidase does not play a role in
viral entry, replication, assembly or budding. J . Virol. 1995, 69,
1099-1106.
(6) von Itzstein, M.; Wu, W.-Y.; Kok, G. B.; Pegg, M. S.; Dyason J .
C.; Phan, T. V.; Smythe, M. L.; White, H. F.; Oliver, S. W.;
Colman, P. M.; Varghese, J . N.; Ryan, D. M.; Woods, J . M.;
J M0002679