884
T. Hanano et al. / Bioorg. Med. Chem. Lett. 10 (2000) 881±884
Table 2. Therapeutic eects of selected compounds in adjuvant
arthritis
Conclusion
Our synthetic investigation to obtain anti-in¯ammatory
agents eective in the chronic in¯ammatory animal
model led to the discovery of the pyrimidylpiperazine
derivative 17c, which showed dual cytokine regulatory
activity (TNF-a suppression and IL-10 augmentation)
in LPS-stimulated mice and an excellent therapeutic
eect in the adjuvant arthritis model. Compound 17c is
expected to be a promising drug candidate for the
treatment of TNF-a associated diseases including RA.
Dose
(mg/kg)
Therapeutic
eect (%)
Dose
(mg/kg)
Therapeutic
eect (%)
2
3
30
30
30
10
10
10
10
10
35
173
80
55
62
144
46
80
8b
8d
10
10
10
10
10
10
10
173
101
142
131
55
12a
17b
4a
4d
4e
4g
12b
12d
17b
17c
17d
163
133
Acknowledgements
We are grateful to Dr. Takashi Horikawa and Miss
Chie Matsushita for pharmacokinetic studies, Mr. Koji
Okuda for toxicological testings, and Mr. Meguru
Murata for pharmacological testings.
References and Notes
1. (a) Macnaul, K. L.; Hutchinson, N. I.; Parsons, J. N.;
Bayne, E. K.; Tocci, M. J. J. Immunol. 1990, 145, 4154. (b)
Brennan, F. M.; Gibbons, D. L.; Mitchell, T.; Cope, A. P.;
Maini, R. N.; Feldmann, M. Eur. J. Immunol. 1992, 22, 1907.
2. Jackson, C. G.; Williams, H. J. Drugs 1998, 56, 337.
3. Hanano, T.; Adachi, K.; Aoki, Y.; Morimoto, H.; Naka,
Y.; Hisadome, M.; Fukuda, T.; Sumichika, H. Bioorg. Med.
Chem. Lett. 10, 875.
4. Compounds 2a±h, 6a±e, 11a±c, 15a±c, and 19a±c gave
satisfactory analytical and spectroscopic data in accord with
their assigned structures.
5. The log P values were calculated using the well authorized
program, PROLOGP contained in the PALLAS 1.2 package,
a product of CompuDrug Chemistry Ltd (Budapest, Hun-
gary).
Figure 2. Dose-dependent therapeutic eect of 17c in adjuvant
arthritis.
6. It has been reported that there is a good relationship
between membrane permeability and log P in the following
paper. Komiya, I.; Park, J. Y.; Kamani, A.; Ho, N. F. H.;
Higuchi, W. I. Int. J. Pharm. 1980, 4, 249.
7. Pharmacokinetic parameters were calculated according to
our previous method.3
8. In order to investigate the eect of the absolute con®gura-
tion of the racemic 8b on the biological activity, we synthe-
sized (R)-8b and (S)-8b starting from optically pure (R)- and
(S)-phenethylamine, respectively [(R)-8b: [a]2d5+85.9 (c1.00,
CHCl3), (S)-8b: [a] 2d5 87.7 (c1.00, CHCl3)]. We found that the
enantiomers have no signi®cant dierence in the activity
[TNF-a (% inhibition) (R)-8b: 80%, (S)-8b: 79%; IL-10 (% of
control) (R)-8b: 499%, (S)-8b: 413%)].
therapeutic eectiveness increased upon increasing the log
P values (1.23, 1.76, and 2.01, respectively). Compound
17c, a cyclopropyl derivative of compound 4e, shows a
good therapeutic eect, suggesting that the modi®cation
of the methylene group between the acetamido group
and the middle benzene group with the cyclopropyl
group led to a signi®cant increase in therapeutic eec-
tiveness. The improved log P value (0.75) of 17c com-
pared with that of 4e re¯ects its good bioavailability
(76% at a dose of 30 mg/kg in rats). Compounds 8b,
12b and 17d also demonstrated an excellent therapeutic
eect in the model.
9. Compound 17c showed no signi®cant adverse eects at up
to 100 mg/kg, po in toxicological studies using rats.
10. It is well known that steroids such as prednisolone have an
excellent anti-in¯ammatory eect on various diseases but they
often show adverse eects (e.g. rebound). It should be possible
to use the dual cytokine regulators with steroids (at low doses
where steroids do not show adverse eects) at the same time
because these two agents have totally dierent mechanisms of
action. For example, rebound has been observed in a collagen
induced arthritis model in rats; see the following reference.
Yamaki, K.; Nakagawa, H.; Tsurufuji, S. Ann. Rheum. Dis.
1987, 46, 543
We chose compound 17c for further pharmacological
examination because it possessed the most favorable
toxicological pro®le among the compounds (3, 4g, 12b,
12d, 17c and 17d) that had shown a good therapeutic
eect.9 Compound 17c was evaluated for its therapeutic
eect in the above-mentioned model at three doses (3,
10 and 30 mg/kg, po) along with prednisolone (1 mg/kg,
po)10 as the positive control (Fig. 2). Compound 17c
signi®cantly reduced the increased volumes of both hind
paws of sensitized rats in a dose-dependent manner.