774
M. Fujita et al. / Bioorg. Med. Chem. Lett. 12 (2002) 771–774
methodology as after intravenous administration. As
the results, compound 12 showed 1.6 and 5.2 mg/kg in
both PAF antagonist and TxSI activity, respectively.
Table 5. In vivo PAF antagonist and ex vivo TxA2 synthase inhibi-
tory activities of compounds 1–19
Compd
ED50 (mg/kg iv)
ED50 (mg/kg po)
In conclusion, we have found that several compounds
indicate good dual PAF antagonist/TxSI activity by
intravenous dosing, and that a compound (12) indicate
excellent dual activity by oral dosing. These compounds
appeared to be not parted in the diazepine and the ester
in vivo. Further progress in this work will be the subject
of future reports.
PAF
antagonista
TxA2
synthaseb
PAF
antagonista
TxA2
synthaseb
3
1
2
4
5
6
7
8
9
10
11
12
13
14
15
16
2.4
0.47
0.2
0.2
1.35
4.2
1.05
0.38
4.2
>1.0
>1.0
>1.0
0.1
>10.0
2.3
0.5
NTc
NT
NT
>10.0
>10.0
>10.0
>10.0
>10.0
>10.0
>10.0
>10.0
1.6
>10.0
>10.0
>10.0
>10.0
>10.0
NT
>10.0
>10.0
NT
NT
6.9
1.0
>1.0
>1.0
0.53
>1.0
0.1
0.71
1.0
1.0
0.77
>1.0
>1.0
>1.0
NT
0.01
NT
NT
NT
References and Notes
0.8
>10.0
3.2
5.2
10.0
8.9
NT
NT
NT
NT
>0.1
NT
NT
0.1
0.05
0.60
0.55
0.47
0.54
0.54
0.54
0.54
>5.0
NT
0.02
0.1
NT
NT
1. Braquet, P.; Paubert-Braquet, M.; Koltai, M.; Bourgain,
R.; Bussolino, F.; Hosford, D. Trends Pharm. Sci. 1991, 10,
23.
2. Sanchez-Crespo, M. Drug News Perspect. 1993, 6, 78.
3. (a) Page, C. P. J. Allergy Clin. Immunol. 1988, 81, 144. (b)
Barnes, P. J. J. Allergy Clin. Immunol. 1988, 81, 152.
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Willerson, J. T. N. Engl. J. Med. 1981, 304, 684.
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6. Fitzgerald, D. J.; Roy, L.; Catella, F.; Fitzgerald, G. A. N.
Engl. J. Med. 1986, 315, 983.
17
18
19
NT
0.025
1.55
NT
NT
(ꢁ)-E6123
UK74505
Ozagrel
Isbogrel
0.02
0.01
aActivity in vivo was demonstrated by the ability to protect mice from
the lethal effects of an injection of PAF. The ED50 values represent the
dose reduced mortality by 50%. This was performed according to the
method of Cooper et al. with slight modification.14
7. Fiddler, G.; Lumley, P. Circulation 1990, 81, 69.
8. Fujita, M.; Seki, T.; Inada, H.; Shimizu, K.; Takahama, A.;
Sano, T. Bioorg. Med. Chem. Lett. 2002, 12, 341.
9. For additional data related to this work see: Fujita, M.;
Seki, T.; Inada, H.; Sano, T. J. P. Patent 071378A1, 1999.
10. Preparation of the diazepines, and about E-6123, see:
Miyazawa, S.; Okano, K.; Shimomura, N.; Clark, R. S. J.;
Kawahara, T.; Asano, O.; Yoshimura, H.; Miyamoto, M.;
Sakuma, Y.; Muramoto, K.; Obaishi, H.; Harada, K.;
Kajima, T.; Yamada, K.; Tsunoda, H.; Katayama, S.; Abe, S.;
Asakawa, N.; Souda, S.; Horie, T.; Sato, T.; Machida, Y.;
Katayama, K.; Yamatsu, I. Chem. Pharm. Bull. 1991, 39, 3215.
11. Submitted to Bioorg. Med. Chem. Lett.
12. Terashita, Z.; Imura, Y.; Tanabe, M.; Kawazoe, K.;
Nishikawa, K.; Kato, K.; Terao, S. Thromb. Res. 1986, 41,
223.
13. Terashita, Z.; Tsushima, S.; Yoshioka, Y.; Nomura, H.;
Inada, Y.; Nishikawa, K. Life Sci. 1983, 41, 1975.
14. Cooper, K.; Fray, M. J.; Parry, M. J.; Richardson, K.;
Steele, J. J. Med. Chem. 1992, 35, 3115.
bInhibition of serum TxB2 production in the rats. This was performed
according to the method of Terashita et al. with slight modification.12
cNT=not tested.
1–19 were tested in and ex vivo after intravenous
administration. PAF antagonist activity was assessed in
the mouse, using a PAF-induced death assay.14 As the
results, the ED50 values for all compounds except for 18
and 19 were in the range 0.2–4.2 mg/kg. On the other
hand, TxSI activity was assessed by ex vivo inhibition of
serum TxB2 production in the rat.12 As the results, the
ED50 values for compounds 4–14 except for 6, 7 and 9
were in the range 0.1–1.0 mg/kg, and compound 19 was
0.01 mg/kg.
Furthermore, these representative compounds were tes-
ted in or ex vivo after oral administration by the same
15. Kato, K.; Ohkawa, S.; Terao, S.; Terashita, Z.; Nishi-
kawa, K. J. Med. Chem. 1985, 28, 287.