316
S. Ueda et al. / Bioorg. Med. Chem. Lett. 14 (2004) 313–316
Table 3, both 5d and 6c, given orally, strongly inhibited
the increase in plasma nitrite/nitrate levels in mice (5d:
11. Hansen, D. W.; Peterson, K. B.; Trivedi, M.; Webber, R. K.;
Tjoeng, F. S.; Moore, W. M.; Jerome, G. M.; Kornmeier,
C. M.; Manning, P. T.; Connor, J. R.; Misko, P. T.;
Currie, M. G.; Pitzele, B. S. J. Med. Chem. 1998, 41, 1361.
7
1% at 3 mg/kg, 6c: 75% at 10 mg/kg).
1
2. Hagmann, W. K.; Galdwell, C. G.; Chen, P.; Durette,
P. L.; Esser, C. K.; Lanza, T. J.; Kopka, I. E.; Guthi-
konda, R.; Shah, S. K.; MacCoss, M.; Chabin, R. M.;
Fletcher, D.; Grant, S. K.; Green, B. G.; Humes, J. L.;
Kelly, T. M.; Luell, S.; Meurer, R.; Moore, V.; Pacholok,
S. G.; Pavia, T.; Williams, H. R.; Wong, K. K. Bioorg.
Med. Chem. Lett. 2000, 10, 1975.
3. Conclusion
The series of 1,3-oxazolidin-2-imine derivatives descri-
bed here represents a new class of iNOS inhibitor. The
SARs of these novel inhibitors revealed that introduc-
tion of small substituents into the 1,3-oxazolidine ring
enhances both the inhibitory activity and selectivity for
iNOS. In addition, oral administration of selected 1,3-
oxazolidin-2-imine derivatives attenuates the rise of
plasma nitrite/nitrate levels induced by LPS in mice.
These findings would aid in the design of more potent
and selective iNOS inhibitors, because 1,3-oxazolidin-2-
imine scaffold is easily synthesized from the corre-
sponding amino alcohols and has diversity to introduce
substituent at any position on its ring as well as to
exchange oxygen atom by other one. Further investiga-
tion of the 1,3-oxazolidin-2-imine derivatives as well as
other relative compounds is now in progress.
13. Tinker, A. C.; Beaton, H. G.; Boughton-Smith, N.; Cook,
T. R.; Cooper, S. L.; Fraser-Rae, L.; Hallam, K.; Hamley,
P.; McInally, T.; Nicholls, D. J.; Pimm, A. D.; Wallace,
A. V. J. Med. Chem. 2003, 46, 913.
1
4. Naka, M.; Nanbu, T.; Kobayashi, K.; Kamanaka, Y.;
Komeno, M.; Yanase, R.; Fukutomi, T.; Fujimura, S.;
Seo, H. G.; Fujiwara, N.; Ohuchida, S.; Suzuki, K.;
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5. Young, R. J.; Beams, R. M.; Carter, K.; Clark, H. A. R.;
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Drysdale, M. J.; Franzman, K. W.; French, C.; Hodgson,
S. T.; Hodson, H. F.; Kleanthous, S.; Rider, P.; Sanders,
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comments on this letter.
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14
2
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