M. H. Bolli et al. / Bioorg. Med. Chem. Lett. 13 (2003) 955–959
959
incorporating a 2-butyne-1,4-diol, such as 70, 71, 75,
and 78, show high affinity towards the endothelin
receptors and high functional potency in vitro. They are
about as potent as their corresponding ethylene glycol
analogues disclosed previously.19 Further studies shall
aim at improving the carbamate’s in vivo profile.
Acknowledgements
The authors would like to thank Walter Schmutz, Pas-
cal Rebmann, Udo Diessenbacher, David Monnard,
Josiane Rein, Celine Boukhadra and Helene Hettrich
for their excellent technical support and Prof. Henri
Ramuz for helpful discussions.
Figure 2. Mean arterial blood pressure recordings (MAP) before and
after administration of 30 mg/kg of the propargyl derivative 26 to
hypertensive Dahl salt-sensitive rats (n=5). The heart rate remained
unaffected (data not shown).
References and Notes
1. Yanagisawa, M.; Kurihara, H.; Kimura, S.; Tomobe, Y.;
Kobayashi, M.; Mitsui, Y.; Goto, K.; Masaki, T. Nature 1988,
332, 411.
2. Inoue, A.; Yanagisawa, M.; Kimura, S.; Kasuya, Y.;
Miyauchi, T.; Goto, K.; Masaki, T. Proc. Natl. Acad. Sci.
U.S.A. 1989, 86, 2863.
Table 5. Area between curves (ABC) calculated after oral adminis-
tration of 30 mg/kg of the compounds to hypertensive Dahl salt-sen-
sitive rats (n=5) equipped with a telemetric system recording blood
pressure and heart ratea
3. Webb, M. L.; Meek, T. D. Med. Res. Revs. 1997, 17, 17.
4. Rubanyi, G. M.; Polokoff, M. A. Pharmacol. Rev. 1994, 46,
325.
5. Filep, J. G. Drugs Today 1995, 31, 155.
6. Warner, T. D. Cardiovasc. Drug Rev. 1994, 12, 105.
7. Ohlstein, E. H.; Elliott, J. D.; Feuerstein, G. Z.; Ruffolo,
R. R. Med. Res. Rev. 1996, 16, 365.
8. Clark, W. M. Curr. Opin. Drug Discov. Develop. 1999, 2,
565.
9. Graul, A.; Leeson, P. A.; Castaner, J. Drugs Future 2000,
25, 159.
10. Boss, C.; Bolli, M.; Weller, T. Curr. Med. Chem. 2002, 9,
349.
11. Breu, V.; Coassolo, P.; Huber, R.; Neidhart, W.; Ramuz,
H.; Roux, S.; Wessel, H. P. WO-0042035, 2000.
12. Kohara, Y.; Kubo, K.; Imamiya, E.; Wada, T.; Inada, Y.;
Naka, T. J. Med. Chem. 1996, 39, 5228.
Compd
IC50 ETA
(nM)
IC50 ETB
(nM)
pA2
ABC
Bosentan 1
40
97
85
51
13
14
1
280
1190
3169
832
1140
236
7.14
6.97
7.15
6.83
340
661
508
92
332
25
26
27
29
30
68
70
78
7.70
7.70
8.11
42
241
29
26
2
aA compound with an ABC<100 is considered to be inactive at the
dose tested. The heart rate remained unaffected in all experiments. To
enhance reading the IC50- as well as the pA2-values are given once
more.
rate.22 From the blood pressure recordings, the area
between the curve (ABC) before and the one after
treatment is calculated to assess the compound’s effi-
cacy. Bosentan 1 reaches an ABC of 340 at a dose of
30 mg/kg. At this dose, none of the three carbamates 68,
70, and 78 shows a significant effect on blood pressure.
On the other hand, the propargyl compound 26 (Fig. 2,
Table 5) as well as the 2-butyn-1-ol 27 (Table 5) sig-
nificantly reduce blood pressure despite being con-
siderably less potent in vitro when compared to the
three carbamates 68, 70, and 78. The in vivo activity is
lost with the hydroxy compound 29. However, the in
vivo activity is restored when the free alcohol in 29 is
protected as its methyl ether (30).
13. Pinner, A. J. Liebigs Ann. Chem. 1897, 297, 221.
14. Ashimori, A.; Ono, T.; Uchida, T.; Ohtaki, Y.; Fukaya,
C.; Watanabe, M.; Yokoyama, K. Chem. Pharm. Bull. 1990,
38, 2446.
15. Saikachi, H.; Kitagawa, T. Chem. Pharm. Bull. 1977, 25,
1651.
16. Saikachi, H.; Kitagawa, T.; Nasu, A.; Sasaki, H. Chem.
Pharm. Bull. 1981, 29, 237.
17. Breu, V.; Loffler, B. M.; Clozel, M. FEBS Lett. 1993, 334,
210.
18. Clozel, M.; Breu, V.; Gray, G. A.; Kalina, B.; Loffler,
B.-M.; Burri, K.; Cassal, J.-M.; Hirth, G.; Muller, M.; Neid-
hart, W.; Ramuz, H. J. Pharm. Exper. Ther. 1994, 270, 228.
19. Neidhart, W.; Breu, V.; Burri, K.; Clozel, M.; Hirth, G.;
Klinkhammer, U.; Giller, T.; Ramuz, H. Bioorg. Med. Chem.
Lett. 1997, 7, 2223.
20. Morimoto, H.; Shimadzu, H.; Hosaka, T.; Kawase, Y.;
Yasuda, K.; Kikkawa, K.; Yamauchi-Kohno, R.; Yamada, K.
Bioorg. Med. Chem. Lett. 2002, 12, 81.
21. Morimoto, H.; Shimadzu, H.; Kushiyama, E.; Kawanishi,
H.; Hosaka, T.; Kawase, Y.; Yasuda, K.; Kikkawa, K.;
Yamauchi-Kohno, R.; Yamada, K. J. Med. Chem. 2001, 44,
3355.
In conclusion, sulfonylamido pyrimidine derivatives
incorporating a propargyl side chain in position 6 and a
4-pyridine substituent in position 2 which itself is sub-
stituted with a polar group in position 2, are potent
antagonists of the ETA receptor. In addition, the pro-
pargyl derivative 26 has been shown to reduce blood
pressure in hypertensive Dahl salt-sensitive rats. Pyri-
dine and pyrazine carbamoyl derivatives of compounds
22. Hess, P.; Clozel, M.; Clozel, J.-P. J. Appl. Phys. 1996, 81,
1027.