C. Boss et al. / Bioorg. Med. Chem. Lett. 13 (2003) 951–954
953
Table 3. 5-Methyl-2-pyridylsulfonamides: inhibition of [125I]-ET-1 binding to membranes of CHO-cells expressing the human ETA or ETB receptor
(IC50) and functional inhibitory potency (pA2) preventing the ET-1 induced contraction of rat aortic rings
Compd
R2
R3
n
IC50 (nM)
pA2
ETA
ETB
5660
ETA
ETB
34
35
36
37
38
39
40
41
42
43
Cyclopropyl
Cyclopropyl
Cyclopropyl
4-Pyridyl
4-Pyridyl
4-Pyridyl
Ethyl
Propyl
2-Thienyl
Ethyl
2-Thienyl
4-Tolyl
2-Thienyl
2-Thienyl
Propyl
2
2
2
2
2
2
2
2
2
2
582
13204670
18508240
185
2838
2193
2770351
21902110
51
5402
3676
1537
Trimethoxyphenyl
Piperonyl
Morpholinyl
Morpholinyl
931
447
6.61
5.58
2-Thienyl
724
morpholinyl-, piperazinyl-, piperonyl-, methyl- or
methylsulfanyl-group or a hydrogen atom in position 2
(not depicted in Table 1) which were substantially less
potent in receptor binding assays. With respect to the
substituent at the second sulfonamide unit and the
length n of the spacer, it can be seen that R3=ethyl
gives compounds with moderate to good activity with a
slight preference for the ETA receptor if n=2 (e.g., 10
and 11). This trend is inversed by the introduction of a
longer spacer n=3 (e.g., 15 and 16) and more pro-
nounced in case R2=2-pyrimidinyl although the recep-
tor affinity is in general better with R2=cyclopropyl.
Replacement of the ethyl group by a 2-thienyl group in
position R3 gives rise to more potent receptor antago-
nists (e.g., 12) already slightly selective for the ETB
receptor with n=2. Introduction of the longer spacer
(n=3) in combination with R3=2-thienyl yields com-
pounds 17, with a 7-fold selectivity for the ETB recep-
tor, and 18, exhibiting 24-fold selectivity for the ETB
receptor, with IC50 values in the low nM range. With
respect to functional inhibitory potency, the ETB-
selectivity of compound 17 is close to 200, as reflected
in the pA2 values. Increasing the size of the substituent
R3 does not increase the ETB-selectivity of the com-
pounds but leads to a substantial loss of activity
towards both receptors as reflected by comparison of
compounds 12 versus 14 and 10 versus 13. Introduction
of a methyl-, trifluoromethyl-, isopropyl-, 4-methoxy-
phenyl-, 4-bromophenyl- or 2-pyridyl group as R3
always gives less active ET receptor antagonists (not
depicted in Table 1).
28) and finally to 3,4,5-trimethoxyphenyl (22, 23, 24)
leads to highly potent and selective ETB antagonists.
This is also reflected in the pA2 values of compounds 22,
23 and 24 in the functional assay using rat tracheal
rings. In all three groups of compounds with
R2=cyclopropyl, morpholinyl, and 3,4,5-trimethoxy-
phenyl and n=2, the influence of R3 always exhibits the
same tendencies: smaller groups like ethyl allow some
affinity towards the ETA receptor (e.g., 19 and 25),
whereas increasing the size of substituent R3 from pro-
pyl (e.g., 22) to 2-thienyl (e.g., 23) or 4-tolyl (e.g., 24)
leads to a loss of affinity for the ETA receptor and
simultaneously a gain of affinity for the ETB receptor.
Increasing the length of the spacer between the central
pyrimidine and the second sulfonamide unit by an
additional CH2 group leads to receptor antagonists
exhibiting a flat SAR with respect to ETA affinity. In
this group, ETB affinity seems to be less depending on
the nature of the substituent R2, for example 32
(R2=cyclopropyl) and 33 (R2=morpholinyl) both gave
IC50 values in the range of 20nM. The group of com-
pounds with R2=cyclopropyl and n=3 (29, 30, 31, 32)
show the same SAR tendency for ETB activity as
already observed in Table 1. The best compound, 31,
bearing the 2-thienyl-group, exhibits pA2 values of 6.92
(ETA) and 8.04 (ETB) which indicate the potential
within the group of bis-sulfonamide ET receptor
antagonists.
In Table 3, the 5-isopropyl-2-pyridyl sulfonamide is
replaced by a 5-methyl-2-pyridyl sulfonamide. The IC50
values both towards the ETA and ETB receptor are
substantially lower as of comparable derivatives depic-
ted in Tables 1 and 2. Compounds containing a
5-methyl-2-pyridyl sulfonamide unit in position 4 of the
central pyrimidine are described to be ETA selective
compared to compounds with a 4-tert-butyl-phenyl sul-
fonamide in this position.15,16 Since we had potent and
selective ETB receptor antagonists, we intended to
increase the activity towards the ETA receptor by the
introduction of the 5-methyl-2-pyridyl sulfonamide.
However, the concept valid for ET receptor antagonists
with small substituents in position 6 of the central pyr-
imidine core described earlier was not applicable to our
bis-sulfonamide ET receptor antagonist series.10,15,16
Table 2 gives an overview on the compounds with a
5-isopropyl-2-pyridyl group as the sulfonamide sub-
stituent in position 4 of the central pyrimidine. It can be
seen that the best binding affinities towards the ETA
receptor (e.g., 25, 29 and 31) are in the same range (10
nM<IC50<50nM) as those of compounds 15 and 17
(Table 1) having a 4-tert-butyl-phenyl group instead of
the 5-isopropyl-2-pyridyl group. Within the group of
compounds with the ethyl spacer (n=2), selectivity
towards the ETB receptor strongly depends on the nat-
ure of the substituent in position 2 of the central pyr-
imidinyl unit. Increasing the size of this substituent
from cyclopropyl (19, 20, 21) to morpholinyl (25, 26, 27,