982
T. Troxler et al. / Bioorg. Med. Chem. Lett. 18 (2008) 979–982
Table 4. Compounds 19, ent-19, 30 and ent-30: physicochemical parameters and affinities for different somatostatin receptor subtypes
O
O
O
O
H
H
H
H
H
H
H
H
HN
Br
HN
Br
HN
Br
HN
Br
N
N
N
N
N
N
N
N
N
N
N
N
O
O
N
N
N
N
N
N
O
O
19
Mpb
30
ent-19
ent-30
20
½aꢁD
c
a
Compound
pKd
r sst1
r sst2
h sst1
h sst2
h sst3
h sst4
h sst5
19
275° (decomp.)
250° (decomp.)
266° (decomp.)
260° (decomp.)
ꢀ96.6°
+98.6°
ꢀ82.7°
+84.6°
9.69 0.05
6.38 0.02
9.43 0.10
6.74 0.03
4.71 0.04
4.69 0.02
5.19 0.10
4.90 0.04
8.76 0.01
5.71 0.02
8.91 0.04
6.30 0.01
4.91 0.05
5.03 0.03
5.17 0.05
5.41 0.01
5.53 0.01
5.27 0.04
5.63 0.04
5.14 0.05
5.31 0.05
5.09 0.01
5.44 0.06
5.25 0.03
4.25 0.10
4.16 0.09
5.19 0.01
4.63 0.02
ent-19
30
ent-30
a Mean SEM. Number of experiments: n = 3–6.
b Free base.
c Free base (DMF, c = 0.5).
7. Hurth, K.; Enz, A.; Floersheim, P.; Gentsch, C.; Hoyer,
D.; Langenegger, D.; Neumann, P.; Pfa¨ffli, P.; Sorg, D.;
Swoboda, R.; Vassout, A.; Troxler, T. Bioorg. Med. Chem.
Lett. 2007, 17, 3988.
8. (a) Pfaeffli, P.; Neumann, P.; Swoboda, R.; Stutz, P.
¨
PCT Int. Appl. WO 9854183, 1998; (b) Pfaeffli, P.;
at the blood–brain barrier, 30 readily entered the brain.
Oral administration of 30 lmol/kg 30 to rats led to
brain/plasma ratios ranging from 0.7 after 10 min to
1.7 after 24 h. Details as well as in vivo pharmacology
data will be published elsewhere in due course.
Neumann, P.; Swoboda, R.; Stutz, P. Chem. Abstr.
1998, 130, 25220.
9. Nordmann, R.; Petcher, T. J. J. Med. Chem. 1985, 28, 367.
10. Hoyer, D.; Perez, J.; Schoeffter, P.; Langenegger, D.;
¨
In conclusion, we have identified sst1 antagonists of a
novel ergoline-type structural class with sub-nanomolar
affinities to somatostatin sst1 receptors and >1000-fold
selectivity over other somatostatin receptor subtypes.
They behave as full antagonists in functional assays
and show promising PK properties in rodents.
Schupbach, E.; Kaupmann, K.; Lubbert, H.; Bruns, C.;
¨
¨
Reubi, J. C. Eur. J. Pharmacol. 1995, 289, 151.
11. Schoeffter, P.; Perez, J.; Langenegger, D.; Schupbach, E.;
¨
Lubbert, H.; Bruns, C.; Hoyer, D. Eur. J. Pharmacol.
¨
1995, 289, 163.
12. Stoll, A.; Hofmann, A. Hoppe-Seyler’s Z. Physiol. Chem.
1937, 250, 7.
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