The use of sulfonylamido pyrimidines incorporating an unsaturated side chain as endothelin receptor antagonists

Article abstract of DOI:10.1016/S0960-894X(02)01084-3

A series of compounds structurally related to bosentan 1 featuring an unsaturated side chain at position 6 of the core pyrimidine have been studied for their potential to block the ET_A and ET_B receptor. Incorporation of a 2-butyne-1,4-diol linker bearing a pyridyl carbamoyl moiety led to in vitro highly potent endothelin receptor antagonists (e.g., 70 and 75). The propargyl derivative 26 significantly reduced blood pressure in in vivo model studies with hypertensive salt-sensitive Dahl rats.

Full text of DOI:10.1016/S0960-894X(02)01084-3

Bioorganic & Medicinal Chemistry Letters 13 (2003) 955–959
The Use of Sulfonylamido Pyrimidines Incorporating an
Unsaturated Side Chain as Endothelin Receptor Antagonists
Martin H. Bolli,* Christoph Boss, Martine Clozel, Walter Fischli,
Patrick Hess and Thomas Weller
Drug Discovery Chemistry and Preclinical Research, Actelion Pharmaceuticals Ltd,
Gewerbestrasse 16, CH-4123 Allschwil/BL, Switzerland
Received 25 October 2002; revised 2 December 2002; accepted 3 December 2002
Abstract—A series of compounds structurally related to bosentan 1 featuring an unsaturated side chain at position 6 of the core
pyrimidine have been studied for their potential to block the ETA and ETB receptor. Incorporation of a 2-butyne-1,4-diol linker
bearing a pyridyl carbamoyl moiety led to in vitro highly potent endothelin receptor antagonists (e.g., 70 and 75). The propargyl
derivative 26 significantly reduced blood pressure in in vivo model studies with hypertensive salt-sensitive Dahl rats.
# 2003 Elsevier Science Ltd. All rights reserved.
In 1988, endothelin-1 (ET-1) was isolated from the
supernatant of cultured porcine endothelium cell
monolayers.1 The 21 amino acid peptide was charac-
terised as the most potent vasoconstrictor ever reported.
As it turned out, there are three different endothelins
(ET-1, ET-2, ET-3) in man2 that act through specific
binding to two closely related G-protein coupled recep-
tors, the endothelin receptors ETA and ETB. These
receptors show different selectivities for the three endo-
thelins. While the ETA receptor strongly binds ET-1 and
ET-2 but shows considerably lower affinity towards
ET-3, the ETB receptor does not discriminate among the
three peptides.3 ET-receptors are found in almost all
organs.3,4 However, the ratio of ETA and ETB receptors
varies greatly in the various tissues. Pharmacological
activation of the ETA and ETB receptor leads to a
vasoconstriction. On the other hand, activation of the
ETB receptor can also trigger vasodilation, for example,
due to coupling to NOrelease. Apart from these rather
immediate effects, activation of the ET-receptors has
been reported to induce cell proliferation and to effect
hormone production, and therefore has long term
effects on angiogenesis, inflammation and cardiac and
vascular remodelling.5 A wealth of renal, cardiac as well
as vascular diseases such as renal failure, hypertension,
atherosclerosis, acute myocardial infarction, congestive
heart failure (CHF), pulmonary arterial hypertension
(PAH), or cerebral vasospasm appear to be associated
with elevated levels of endothelins, in particular ET-1.5ꢀ7
The endothelin receptor antagonists are therefore
thought to represent a novel class of drugs to treat such
disorders. Indeed, a first non-peptidic orally active
endothelin receptor antagonist, bosentan 1 (Fig. 1), has
recently been approved for the treatment of pulmonary
arterial hypertension in the USA, Canada, the European
Union and Switzerland. A number of other non-peptidic
endothelin receptor antagonists are in late clinical
trials8ꢀ10 [e.g., atrasentan (Abbott) for prostate cancer
(PC); darusentan (Abbott) for CHF, enrasentan
(GlaxoSmithKline) for CHF; sitaxsentan (Texas-Bio-
technology) for CHF, PAH; T-0201 (Tanabe) for CHF;
Y-598 (Yamanouchi) for PC]. In this paper, we disclose
some of our results on structures related to bosentan 1.
In particular, we focus on the structure–activity–relation-
ship (SAR) of unsaturated side chains replacing the ethy-
lene glycol residue at position 6 of the core pyrimidine.
*Corresponding author. Fax: +41-61-487-4500; e-mail: martin.bolli@
actelion.com
Figure 1.
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(02)01084-3

956
M. H. Bolli et al. / Bioorg. Med. Chem. Lett. 13 (2003) 955–959
In general, the preparation of the compounds 23–78 was
achieved in analogy to literature procedures and is out-
lined in Scheme 1. The necessary key intermediates 5
were prepared via a classical pyrimidine synthesis by con-
densing the corresponding amidines 2 with malonate 3
followed by chlorination of the obtained 4,6-dihydroxy-
pyrimidines 4. The 4,6-dichloropyrimidines 5 were then
reacted with an excess of the sulfonamide potassium
salts to give the 6-chloro-4-sulfonylamino-pyrimidine
derivatives 6. Conversion of the monochlorides 6 to the
desired pyrimidines 7 was effected by treating the chloro
compound with the corresponding alcoholate at ele-
vated temperatures.
Additionally, compounds incorporating a 2-hydroxy-
methyl pyridine substituent at position 2 of the core
pyrimidine have been prepared (Scheme 4). The pivotal
2-methyl-pyridine substituted 4,6-dichloropyrimidine 17
was prepared starting from 2-methyl-4-cyanopyridine
16.14 Compound 17 was then transformed to its pyri-
dine N-oxide 18 by treatment with peracetic acid. The
next steps involved the introduction of the sulfonamide
moiety and the unsaturated side chain. The N-oxide 19
smoothly rearranged in refluxing acetic anhydride14 to
the corresponding acetoxymethyl pyridine derivative
which upon hydrolysis yielded the desired hydroxy-
methyl pyridine 20.
A number of compounds incorporating a five-mem-
bered heterocycle at the 2-position of the pyridine at
position 2 of the core pyrimidine have been studied
(Scheme 2, Table 4). Their preparation starts from the
nitrile 8.11 Prior to the assembly of the heterocycle, the
sulfonamide part was introduced by treating compound
8 with the corresponding sulfonamide potassium salt.
The 4H-5-oxo-[1,2,4]oxa-diazole and the 4H-5-thio-
[1,2,4]oxadiazole ring was built up in a two-step pro-
cess.12 Upon treatment with sodium methylate, the
nitrile in compound 9 transformed to the iminoether
which was then quenched with hydroxylamine hydro-
chloride to give the amidoxime 10. Smooth ring closure
to the corresponding oxadiazoles 11 was achieved by
reacting 10 with either carbonyl diimidazole or thio-
carbonyl diimidazole. Substitution of the chlorine in
position 6 of 11 with the appropriate alcoholate com-
pleted the synthesis of the tetrasubstituted pyrimidines
12. On the other hand, treating compound 9 with an
excess of hydrazine hydrate furnished the amidrazones
13 which were then efficiently transformed to the tetra-
zole derivatives 14 under rather mild conditions using
sodium nitrite (Scheme 3).13 As mentioned above the
synthesis was completed by the introduction of the
unsaturated side chain.
The free alcohol functionality of the butynediol deriva-
tives 21 was further reacted with an isocyanate in the
presence of DMAP to furnish the corresponding carba-
mates 22 in good yields (Scheme 5). In case R3 repre-
sents a pyridine or pyrazine, the necessary isocyanate
was generated in situ prior to the addition of the alcohol
21 from the corresponding carboxylic acid azide15,16 in
refluxing chloroform.
Scheme 2. Reagents and conditions: (a) 1.5 equiv R1SO2NHK, 1 equiv
Hunig’s base, DMSO, rt 18–48 h, 72–92%; (b) (i) 1.3 equiv NaOMe,
MeOH, 45 ꢁC 24 h; (ii) 1.3 equiv NH2OH.HCl, 45 ꢁC 15 min, 77–93%;
(c) (X¼O) 1.1 equiv Im2CO, 4 equiv DBU or DBN, MeCN, rt 48–72 h,
67–78%; (d) (X¼S) 1.1 equiv Im2CS, 4 equiv DBU or DBN, MeCN, rt
48–72 h, 62–78%; (e) 10–20 equiv NaH, 40–80 equiv R2OH, THF,
DMF, 60–80 ꢁC 16–24 h, 57–74%.
Scheme 1. General reaction pathway for the preparation of 4-sulfo-
nylamino pyrimidines. Reagents and conditions: (a) 3 equiv NaOMe,
MeOH, rt, 18 h, 80–100%; (b) POCl3, PhNMe2, 120 ꢁC, 2–18 h,
50–90%; (c) R2SO2NHK, DMSOor DMF, rt to 60 ꢁC, 18–72 h,
50–95%; (d) R3ONa, R3OH, neat or in DME, DMF or DMPU,
60–120 ꢁC, 4–48 h, 30–95%.
Scheme 3. (R, R1 as in Scheme 2) Reagents and conditions: (a) 4 equiv
NH2NH.2HCl or NH2NH.2H2O, DMF, rt 24–72 h, 69–99%; (b)
1.83 equiv NaNO2, concd HCl/H2O, DMF, rt 2 h, 82–95%; (c) 10 eq.
NaH, 40–60 equiv R2OH, THF, DMF, 55–80 ꢁC 3–18 h, 52–64%.

M. H. Bolli et al. / Bioorg. Med. Chem. Lett. 13 (2003) 955–959
957
Scheme 5. Reagents and conditions: (a) 1–2-equiv R3NCO, 0.5–1
equiv DMAP, CHCl3, 75 ꢁC 18 h, 43–89%; or (i) 2.5–4 equiv R3CON3,
1 equiv DMAP, CHCl3, 75 ꢁC 1–2 h; (ii) addition of 21, 75 ꢁC 18 h,
58–76%.
triple bond (26–29) are about four times more potent
when compared to the allylic derivatives. Compound 29
incorporating the 2-butyne-1,4-diol is about as potent as
bosentan 1. Interestingly, masking the terminal alcohol
functionality in 29 with a methyl group (30) improves
the compound’s affinity towards the ETA receptor. The
phenyl ether 31 and in particular the benzyl ether 32,
however, show poorer IC50-values for the ETA receptor
blockade. It is noteworthy that the benzylether side
chain in 32 leads to a compound preferentially blocking
the ETB receptor.
Scheme 4. Reagents and conditions: (a) 0.1 equiv NaOMe, 1.1 equiv
NH4Cl, MeOH, rt 24 h, 60–72%; (b) 3 equiv NaOMe, 1.1 equiv 3,
MeOH, rt 16 h, 71%; (c) POCl3, 120–145 ꢁC 12–16 h, 45–56%; (d)
3 equiv CH3COOOH, MeCN, 95 ꢁC 48 h, 68–95%; (e) 2.2 equiv
R1SO2NHK, DMSO, rt 24 h, 60–95%; (f) 10 equiv NaH, 40–60 equiv
R2OH, DMF, THF, 70 ꢁC 18 h, 78–87%; (g) (i) Ac2O, 140 ꢁC
ꢁ
45–90 min; (ii) 0.2 N NaOH, THF, MeOH, H2O , 0 C 1 h, 45–62%.
The receptor affinities (IC50 values) were determined in
radio-ligand competition binding studies on membranes
of CHOcells expressing the human recombinant ET A or
ETB receptor using 125I-labelled ET-1 as described ear-
lier.17 The functional inhibitory potency on ETA recep-
tors (pA2 values) of the compounds was assessed by
their inhibition of the contraction induced by ET-1 on
rat aortic rings.18 All compounds behaved as competi-
tive antagonists.
The series incorporating a propargyl or a butyne-1,4-
diol side chain have been investigated in more detail.
While we have been evaluating a number of sub-
stitutents at position 2 of the core pyrimidine, we
focused our studies on the 4-tert-butylbenzene, the
5-isopropyl-2-pyridine and the 5-methyl-2-pyridine sul-
fonamides as these have been found to furnish the most
promising compounds.19ꢀ21 The examples in Tables 2
and 3 illustrate the effect of the sulfonamide and the
2-substituent on the SAR of the tetrasubstituted
pyrimidines.
First, a number of olefinic and propargylic alcohols
have been introduced to position 6 of the core pyr-
imidine. As shown in Table 1, the side chains incorpor-
ating a double bond give compounds (23–25) inferior in
potency to bosentan 1, although the in vitro potency on
the ETA receptor gradually improves with increasing
chain length. The corresponding compounds with a
Table 2. Inhibition of [125I]-ET-1 binding to membranes of CHO
cells expressing the ETA or ETB receptor
Table 1. Inhibition of [125I]-ET-1 binding to membranes of CHO-
cells expressing the ETA or ETB receptor
Compd
Scaffold
R
IC50 ETA
(nM)
IC50 ETB
(nM)
Compd
R
IC50 ETA IC50 ETB
(nM)
(nM)
29
33
34
35
36
37
38
39
40
41
42
43
A
A
A
A
B
B
B
B
C
C
C
C
2-Pyrimidyl
4-Pyridyl
4-Morpholinyl
Hydrogen
2-Pyrimidyl
4-Pyridyl
4-Morpholinyl
Hydrogen
2-Pyrimidyl
4-Pyridyl
4-Morpholinyl
Methyl
51
125
155
561
53
26
16
166
339
22
832
44
50
744
2030
77
49
183
Bosentan 1
–CH2CH2OH
–CH2CH¼CH2
40
373
239
165
97
85
59
51
13
280
2085
3330
2970
1190
3169
2280
832
23
24
25
26
27
28
29
30
31
32
–CH2CH¼CH–CH3
–CH2CH¼CH–CH2–CH3
–CH2–CꢂCH
–CH2–CꢂC–CH3
–CH2–CꢂC–CH2–CH3
–CH2–CꢂC–CH2–OH
–CH2–CꢂC–CH2–OCH3
–CH2–CꢂC–CH2–O–C6H5
–CH2–CꢂC–CH2–O–CH2–C6H5
>10,000
1520
612
1140
973
199
18
452
139
1280
2880
Values represent results of single experiment.
Values represent results of single experiment.

958
M. H. Bolli et al. / Bioorg. Med. Chem. Lett. 13 (2003) 955–959
Table 3. Inhibition of [125I]-ET-1 binding to membranes of CHO
cells expressing the ETA or ETB receptor
Table 4. Inhibition of [125I]-ET-1 binding to membranes of CHO-
cells expressing the ETA or ETB receptor
Compd
Scaffold
R
IC50 ETA
(nM)
IC50 ETB
(nM)
pA2
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
A
A
B
B
B
2-Pyridyl
2-Pyrazinyl
n-Butyl
293
204
157
35
7
14
13
1
0.4
196
753
18
1
21
12
2
1060
1400
18
6.37
6.25
7.57
7.70
6.68
7.70
7.58
Phenyl
32
2-Pyridyl
2-Pyrazinyl
Phenyl
2-Pyridyl
2-Pyrazinyl
n-Butyl
Cyclohexyl
Phenyl
2-Pyridyl
3-Pyridyl
4-Pyridyl
2-Pyrazinyl
123
236
28
42
13
207
603
589
197
920
656
241
Compd
Scaffold
R
IC50 ETA
(nM)
IC50 ETB
(nM)
B
C
C
C
D
D
D
D
D
D
D
26
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
A
A
A
A
A
A
B
B
B
B
B
B
B
B
C
C
C
C
C
C
2-Pyrimidyl
2-Pyrazinyl
4-Pyridyl
I
97
186
176
38
66
84
1190
903
295
100
238
258
1950
2620
823
746
205
294
366
6.64
7.56
6.30
7.29
8.11
II
III
2-Pyrimidyl
2-Pyrazinyl
4-Pyridyl
4-Morpholinyl
96
339
125
121
24
22
27
23
339
94
11
13
12
5
Values represent results of single experiment. pA2-values on rat aortic
rings (n ꢃ2).
I
II
III
IV
2-Pyrimidyl
4-Pyridyl
I
221
>10000
4580
>1000
2500
1670
1030
Note also the trend of selectivity for the ETB receptor
observed with the derivatives 33 and 34 (Table 2).
However, based on these results no rules to achieve ETB
receptor selectivity can be postulated.
II
III
IV
Values represent results of single experiment.
When the butyne-diol linker was further derivatised to
form a carbamate, highly potent compounds could be
identified. The SAR of such carbamates is illustrated in
Table 4. While the n-butyl and cyclohexyl carbamates
65, 72, and 73 exhibit inferior binding affinities when
compared to the corresponding compounds with the
free alcohol moiety (37, 42), the phenyl carbamates 69
and 74 are about as potent as their corresponding free
alcohols 38 and 42, respectively. The affinity towards
the ETA receptor could be improved further when pyri-
dine carbamates were employed. However, the position
of the nitrogen appears to be critical. While the 3-pyri-
dine and 4-pyridine carbamates show moderate
potency, the 2-pyridine derivatives clearly give the best
results (e.g., 75–77). The 2-pyrazine carbamate furnishes
compounds with potencies comparable to those of the
2-pyridine derivatives (e.g., 78). The high affinity of
compounds 70, 75, and 78 in the binding assay is also
reflected in good pA2-values on rat aortic rings. Sur-
prisingly, the 2-pyridine as well as the 2-pyrazine car-
bamate yield rather poor ET-receptor antagonists in
combination with the 2-pyrimidin-2-yl-pyrimidine scaf-
fold A.
In the butyne-1,4-diol series, the combination of R
representing a 4-pyridyl or a 4-morpholine residue with
a pyridine sulfonamide gives the most potent com-
pounds (37, 38, 41, 42). This finding, however, does not
fully translate to the propargyl series (Table 3). Here,
the above combination furnishes compounds with
somewhat inferior potency than the 2-pyrimid-2-yl-pyr-
imidine derivatives 26, 49 and 57. The most potent
examples in the propargyl series are all characterised by
a 2-pyridin-4-yl-pyrimidine scaffold where the pyridine
bears a polar group in position 2. In fact, the tetrazole
at this position yields as good results as the bioisosteric
4H-[1,2,4]oxadiazoles (56 vs 54, 55; 62 vs 60, 61). Sur-
prisingly, in this study the much smaller hydroxy-
methylene group in 46, 53 and 59 appears to be an
equipotent replacement for such polar five-membered
rings.
Interestingly, in both the propargyl as well as the
butyne-1,4-diol series the compounds incorporating the
5-methyl-2-pyridine sulfonamide are as potent inhibi-
tors of ETA but about ten times less potent on ETB as
the corresponding 5-isopropyl-2-pyridine sulfonamide
derivatives. Compounds 40 and 57, both basing on the
2-pyrimid-2-yl-pyrimidine scaffold appear to be the only
exceptions to this rule.
A number of in vitro highly potent compounds have
been screened for their in vivo activity in the rat. Hence,
30 mg/kg of the compound was administered orally to
hypertensive Dahl salt-sensitive rats equipped with a
telemetric system recording blood pressure and heart

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.