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a-hydroxyl group of HMC-hydrazide inhibitors. The
corresponding compound 10 showed 100-fold higher
activity than original 7a. This is consistent with pre-
viously published results.12,13
Maroun, V.; Nguyen, A.; Mimoto, T.; Ueno, T.; Shintani, M.;
Falloon, J.; Masur, H.; Hayashi, H.; Erickson, J.; Mitsuya, H.
Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 8675.
2. Bold, G.; Fassler, A.; Capraro, H. G.; Cozens, R.; Klim-
kait, T.; Lazdins, J.; Mestan, J.; Poncioni, B.; Rosel, J.; Stover,
V.; Tintelnot-Blomley, M.; Acemoglu, F.; Beck, W.; Boss, B.;
Eschbachm, M.; Hurlimann, T.; Masso, E.; Roussel, S.; Ucci-
Stoll, K.; Wyss, D.; Lang, M. J. Med. Chem. 1998, 41, 3387.
3. (a) Mimoto, T.; Kato, R.; Takaku, H.; Nojima, S.; Tera-
shima, K.; Misawa, S.; Fukazawa, T.; Ueno, T.; Sato, H.; Shin-
tani, M.; Kiso, Y.; Hayashi, H. J. Med. Chem. 1999, 42, 1789. (b)
Mimoto, T.; Kato, R.; Takaku, H.; Misawa, S.; Fukazawa, T.;
Nojima, S.; Terashima, K.; Sato, H.; Shintani, M.; Kiso, Y.;
Hayashi, H. In Peptide Science—Present & Future, Shimo-
nishi, Y., Ed.; Kluwer Academic, 1999, p 652. (c) Kiso, Y.
J. Synth. Org. Chem., Jpn. 1998, 56, 896.
4. (a) Mimoto, T.; Hattori, N.; Takaku, H.; Kisanuki, S.;
Fukazawa, T.; Terashima, K.; Kato, R.; Nojima, S.; Misawa,
S.; Ueno, T.; Imai, J.; Enomoto, H.; Tanaka, S.; Sakikawa,
H.; Shintani, M.; Hayashi, H.; Kiso, Y. Chem. Pharm. Bull.
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moto, H.; Hattori, N.; Akaji, K.; Kiso, Y. Chem. Pharm. Bull.
1992, 40, 2251.
5. Erickson, J.; Neidhart, D. J.; VanDrie, J.; Kempf, D. J.;
Wang, X. C.; Norbeck, D. W.; Plattner, J. J.; Rittenhouse,
J. W.; Turon, M.; Wideburg, N.; Kohlbrenner, W. E.; Sim-
mer, R.; Helfrich, R.; Paul, D. A.; Knigge, M. Science 1990,
249, 527.
6. Kempf, D. J.; Norbeck, D. W.; Codacovi, L.; Wang, X. C.;
Kohlbrenner, W. E.; Wideburg, N. E.; Paul, D. A.; Knigge,
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In spite of the potent enzyme inhibitory activity
observed, most of the derivatives showed moderate
antiviral activity with the EC50 values of about 1 mM
against HIV-1 IIIB strain. This large difference is prob-
ably related to the physicochemical features of these
compounds such as solubility and cell-penetration. A
similar observation has been reported for KNI-727.
This molecule, which has a dimethylphenoxyacetyl
group, exhibits a high binding affinity towards the pro-
tease, but low antiviral activity due to its hydro-
phobicity.3,9 In an effort to increase the hydrophilicity
of KNI-727, a 4-amino group was introduced into the
2,6-dimethylphenoxyacetyl group.14 The same approach
was used in synthesizing compound 7e. Intoduction of a
p-amino-2,6-dimethylphenoxyacetyl group showed a
two-fold improvement in antiviral activity. The cyto-
toxicity of synthetic compounds against MT-4 cells was
>10 mM (TD50) and the values of selectivity index (SI)
were >50 in compounds 7a, 7e, 9a, 9b and 10. More
extensive modification of the structure around the
HMC-hydrazide core will be explored to achieve
increased antiviral potency and SI values. Additional
work is underway to assess the inhibitory potency of
this new series against resistant viruses.
In conclusion, we have designed and synthesized novel
pseudo-symmetric HIV-1 protease inhibitors containing
HMC-hydrazide isostere, which effectively inhibited
HIV-1 protease and viral replication in vitro. This
HMC-hydrazide isostere promises to be a useful tem-
plate for the development of novel agents for the treat-
ment of HIV and for the design of inhibitors against
other aspartic proteases.
7. Sham, H. L.; Betebenner, D. A.; Zhao, C.; Wideburg, N. E.;
Saldivar, A.; Kempf, D. J.; Plattner, J. J.; Norbeck, D. W. J.
Chem. Soc., Chem. Commun. 1993, 13, 1052.
8. Fassler, A.; Bold, G.; Capraro, H. G.; Cozens, R.; Mestan,
J.; Poncioni, B.; Rosel, J.; Tintelnot-Blomley, M.; Lang, M. J.
Med. Chem. 1996, 39, 3203.
9. (a) Kiso, Y.; Matsumoto, H.; Mizumoto, S.; Kimura, T.;
Fujiwara, Y.; Akaji, K. Biopolymers 1999, 51, 59. (b) Kiso, Y.;
Yamaguchi, S.; Matsumoto, H.; Mimoto, T.; Kato, R.;
Nojima, S.; Takaku, H.; Fukazawa, T.; Kimura, T.; Akaji, K.
Arch. Pharm. Pharm. Med. Chem. 1998, 331, 87.
Acknowledgements
10. Sham, H. L.; Zhao, C.; Stewart, K. D.; Betebenner, D. A.;
Lin, S.; Park, C. H.; Kong, X.-P.; Rosenbrook, W., Jr.; Her-
rin, T.; Madigan, D.; Vasavanonda, S.; Lyons, N.; Molla, A.;
Kempf, D. J.; Plattner, J. J.; Norbeck, D. W. J. Med. Chem.
1996, 39, 392.
11. Kempf, D. J.; Marsh, K. C.; Paul, D. A.; Knigge, M. F.;
Norbeck, D. W.; Kohlbrenner, W. E.; Codacovi, L.; Vasa-
vanonda, S.; Bryant, P; Wang, X. C.; Wideburg, N. E.; Clem-
ent, J. J.; Plattner, J. J.; Erickson, J. Antimicrob. Agents
Chemother. 1991, 35, 2209.
12. Mimoto, T.; Imai, J.; Tanaka, S.; Hattori, N.; Kisanuki,
S.; Akaji, K.; Kiso, Y. Chem. Pharm. Bull. 1991, 39, 3088.
13. Kiso, Y. Biopolymers 1996, 40, 235.
14. Tanaka, Y.; Matsumoto, H.; Kimura, T.; Akaji, K,; Kiso,
Y. Abstacts of Papers, Part 2, 119th Annual Meeting of the
Pharmaceutical Society of Japan, 29–31 March 1999, p 172.
We would like to thank Dr. W. E. Kohlbrenner and
Dr. S. N. Rajesh for useful discussion. We gratefully
acknowledge the technical assistance of Ms. Y. Matsui
in the determination of HIV-1 protease inhibitory
activity.
References and Notes
1. (a) Yoshimura, K.; Kato, R.; Kavlick, M. F.; Nguyen, A.;
Maroun, V.; Maeda, K.; Hussain, K. A.; Ghosh, A. K.; Gul-
nik, S. V.; Erickson, J. W.; Mitsuya, H. J. Virol. 2002, 76,
1349. (b) Yoshimura, K.; Kato, R.; Yusa, K.; Kavlick, M. F.;