1264
L. Revesz et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1261±1264
14. AA: adjuvant induced arthritis. Female Wistar rats were
References and Notes
immunized with Mycobacterium tuberculosis at day 0 and
dosed with the compounds (2Â25 mg/kg po per day) from day
14±20. Swelling of the joints was measured on day 20.
15. CIA:collagen induced arthritis. Female (WAGÂBUF/F1)
rats were immunized intradermally with bovine nasal septum
type II collagen emulsi®ed in Freund`s incomplete adjuvant.
Compound 11 was dosed twice daily for 10 days after the
onset of swelling.
16. Phosphorylated forms of His-p38b2, His-p38d, His-JNK1
and His-JNK2 MAP kinases of human origin phosporylated
the immobilised substrate GST-ATF-2 in the presence of
cold ATP (120 mM). Antibody detected phosphorylated GST-
ATF-2.
1. Herlaar, E.; Brown, Z. Molecular Medicine Today 1999, 5, 439.
2. Kumar, S.; McDonnell, P. C.; Gum, R. J.; Hand, A. T.;
Lee, J. C.; Young, P. R. Biochem. Biophys. Res. Commun.
1997, 235, 533.
3. Lee, J. C.; Blumenthal, M. J.; Laydon, J. T.; Tan, K. B.;
DeWitt, D. L. 7th International Conference of the In¯amma-
tory Research Association; Poconos, PA, 1994. Lin, W. W.;
Chen, B. C. Br. J. Pharmacol. 1999, 126, 1419.
4. Badger, A. M.; Bradbeer, J. N.; Votta, B.; Lee, J. C.;
Adams, J. L.; Griswold, D. E. J. Pharmacol. Exp. Ther. 1996,
279, 1453. Lee, J. C.; Kassis, S.; Kumar, S.; Badger, A.;
Adams, Jerry L. Pharmacol. Ther. 1999, 82, 389.
5. 1: GP054086. Fitzi, K. DE 2221546, 1972; Chem. Abstr.
1972, 78, 58428.
6. Borsch-Haubold, A. G.; Pasquet, S.; Watson, S. P. J. Biol.
Chem. 1998, 273, 28766.
7. A phosphorylated form of His-p38a MAP kinase (10 ng/
well) of murine origin was used and immobilised GST-ATF-2
as substrate in the presence of 120 mM cold ATP.
17. A phosphorylated form of murine ERK2 MAP kinase
phosphorylated a peptide in the presence of cold and 0.1 mCi
of (32P)g-ATP. MKK6b(EE) kinase: An active form of GST-
MKK6b(EE) of human origin phosporylated the immobilised
substrate GST-p38a(K>M) in the presence of cold ATP (12
mM). EGFR kinase: puri®ed human EGFR-ICD, 400 nM cold
ATP, poly (EY) as substrate and 0.1 mCi of (32P)g-ATP. C-abl:
murine enzyme, cold ATP (5 mM), poly(AEKY) as substrate
and 0.06 mCi of (32P)g-ATP. C-src: activated chicken kinase
20mM, cold ATP, poly (EY) as substrate and 0.07 mCi of
(32P)g-ATP. PKCꢀ: bovine kinase, 10 mM cold ATP, substrate
protamine sulfate and 0.1 mCi of (32P)g-ATP.
8. COX-1 from ram seminal vesicles (Nr. 60100; Cayman
Chemical Company) was used and PGE2 determined by RIA.
9. Shewchuk, L.; Hassell, A.; Wisely, B.; Rocque, W.; Holmes,
W.; Veal, J.; Kuyper, L. F. J. Med. Chem. 2000, 43, 133. Lis-
nock, J. M.; Tebben, A.; Frantz, B.; O'Neill, E. A.; Croft, G.;
O'Keefe, S. J.; Li, B.; Hacker, C.; de Laszlo, S.; Smith, A.;
Libby, B.; Liverton, N.; Hermes, J.; LoGrasso, P. Biochem-
istry 1998, 37, 16573.
10. Human peripheral blood mononuclear cells from healthy
volunteers were incubated with the inhibitor and stimulated
with LPS/IFN-g for 3 h. The supernatants were collected for
TNF-a determination by ELISA.
11. Eight-week old female OF1 mice were dosed perorally by
gavage with solutions of the compounds in DMSO/cornoil. One
hour after dosing, LPS (20 mg/kg) was injected iv for stimulation
of TNF-a release into plasma. One h later blood was collected
and TNF-a was determined using a mouse speci®c ELISA.
12. Compound 8 was dosed at 1 mg/kg iv and 20 mg/kg po.
Compound 11 was dosed at 3 mg/kg iv and 10 mg/kg po.
13. Cmax: maximal plasma concentration after oral dose (8:
20 mg/kg po. 11 mg/kg po).
18. Crespi, C. L.; Miller, V. P.; Penman, B. W. Anal. Biochem.
1997, 248, 188.
19. Adams, J. L.; Boehm, J. C.; Kassis, S.; Gorycki, P. D.;
Webb, E. F.; Hall, R.; Sorenson, M.; Lee, J. C.; Ayrton, A.;
Griswold, D. E.; Gallagher, T. F. Bioorg. Med. Chem. Lett.
1998, 8, 3111.
20. Gallagher, T. F.; Seibel, G. L.; Kassis, S.; Laydon, J. T.;
Blumenthal, M. J.; Lee, J. C.; Lee, D.; Boehm, J. C.; Fier-
Thompson, S. M. Bioorg. Med. Chem. 1997, 5, 49.
21. Revesz, L. WO 9901449, 1999; Chem. Abstr. 1999, 130,
125072.
22. Bredereck, H.; Gompper, R. Chem. Ber. 1954, 87, 700.
23. Severin, T.; Poehlmann, H. Chem. Ber. 1977, 110, 491.
24. Teitei, T. Aust. J. Chem. 1980, 33, 605.
25. De Laszlo, S. E.; Chang, L. L.; Kim, D.; Mantlo, Nathan
B. WO 9716442, 1997; Chem. Abstr. 1997, 127, 50543.