Nonpeptide endothelin antagonists: From lower affinity pyrazol-5-ols to higher affinity pyrazole-5-carboxylic acids

Article abstract of DOI:10.1016/S0960-894X(00)00232-8

Random screening of compounds in endothelin receptor (ET(A) and ET(B)) binding assays led to the discovery of a new class of pyrazol-5-ol ligands. Characterization of structural features crucial for binding activities of these pyrazol-5-ols, by structure-activity-relationship (SAR) studies, allowed us to design a novel class of pyrazole-5-carboxylic acids as more potent ET antagonists. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00232-8

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1351±1355
Nonpeptide Endothelin Antagonists: from Lower Anity
Pyrazol-5-ols to Higher Anity Pyrazole-5-carboxylic Acids
Jidong Zhang,a,* Stanislas Didierlaurent,a Michel Fortin,b Dominique Lefrancois,a
Eric Uridata and Jean Paul Veverta
aMedicinal Chemistry, Hoechst Marion Roussel, 102 route de Noisy, 93235 Romainville Cedex, France
bCentral Research, Hoechst Marion Roussel, 102 route de Noisy, 93235 Romainville Cedex, France
Received 26 January 2000; accepted 17 April 2000
AbstractÐRandom screening of compounds in endothelin receptor (ETA and ETB) binding assays led to the discovery of a new
class of pyrazol-5-ol ligands. Characterization of structural features crucial for binding activities of these pyrazol-5-ols, by struc-
ture±activity-relationship (SAR) studies, allowed us to design a novel class of pyrazole-5-carboxylic acids as more potent ET
antagonists. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
These pyrazol-5-ols are structurally di€erent from most
of the other endothelin antagonists reported in the lit-
erature.8 We wish to describe herein the synthesis and
SAR studies of this pyrazol-5-ol series, which led us to
the more potent pyrazole-5-carboxylic acid series.
The endothelins (ET-1, 2 and 3) constitute a family of
homologous 21-amino acid peptides, with ET-1 being
one of the most potent vasoconstrictors identi®ed to
date.1 Although originally isolated from endothelial
cells, these peptides are also produced by a number of
other cell types.2 The ETs exert their biological e€ects by
interacting with at least two speci®c G-protein coupled
membrane receptors (ETA and ETB) which are di€er-
entiated by their relative anities for these peptides.3
ETA receptors are mainly found in the vascular smooth
muscle tissues and can mediate both vasodilation4 or
vasoconstriction,5 depending on their tissue localiza-
tion. As a result of their potent and long-lasting vaso-
constrictor e€ects, endothelin receptor blockade has
been proposed as a target for therapeutic intervention in
numerous diseases, such as myocardial infarction,
hypertension, heart failure, atherosclerosis, cerebral and
coronary vasospasm, acute renal failure and asthma.6
The discovery of both potent subtype selective and non-
selective ET antagonists should be extremely useful in
clarifying the physiological and pathological roles of
endothelins, and thereby providing useful chemother-
apeutic agents.7
Chemistry
The pyrazol-5-ol compounds used in this study were
prepared by two methods outlined in Scheme 1.9 All the
3-poly¯uoroalkyl pyrazol-5-ols 5±25 (Tables 1±4) were
synthesized by route A: the commercially available b-
ketoesters 1 were deprotonated by NaH in toluene and then
alkylated with the appropriate benzyl halides in the pre-
sence of NaI, using aliquat-336 as phase transfer agent. The
corresponding a-alkylated b-ketoesters 2 were then re¯uxed
in acetic acid with the appropriate salt-free benzyl hydra-
zines to a€ord the desired pyrazol-5-ols 5±25. The salt-
free benzyl hydrazines were obtained by neutralization with
NaOH (1N) in water of the corresponding benzyl hydra-
zine hydrochlorides which were prepared according to a
literature method.10 The other pyrazol-5-ols 26±29 (Table
4) were prepared by route B: the commercially available
b-ketoesters 1 were transformed to the corresponding
pyrazolones 3 under similar conditions to the second step
of route A. Re¯uxing of these pyrazolones 3 with piperonal
in toluene in the presence of ZnCl2 as catalyst a€orded the
compounds 4, which were hydrogenated over Pd/C in
ethyl acetate, to yield the ®nal pyrazol-5-ols 26±29.
The screening of our in house compound library on ET
receptor binding assays allowed us to identify a series of
pyrazol-5-ols with modest anities to both ETA and
ETB subtypes.
Several O-alkylated derivatives 5a±f of pyrazol-5-ol 5
were prepared as depicted in Scheme 2. Alkylation of 5
*Corresponding author. Tel.: +33-1499-14731; Fax: +33-1499-15087;
e-mail: jidong.zhang@aventis.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00232-8

1352
J. Zhang et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1351±1355
with methyl iodide, ethyl bromoacetate, ethyl 4-bromo-
butyrate and 2-bromoethanol in the presence of K2CO3
in DMF a€orded the compounds 5a,b,d,f respectively.
The acids 5c and 5e were obtained by saponi®cation of
corresponding 5b and 5d with NaOH (2N) in ethanol.
competition assays.9 Despite the large number of pyr-
azol-5-ols tested before starting this work, only a few
compounds (Table 2: 5, 6 and 7; Table 3: 15) were
identi®ed by initial screening as weak endothelin receptor
ligands, with IC50s superior to 1 mM. They all contained
a 3-tri¯uoromethyl group and two di€erent substituted
benzyl groups at position 1 and 4 of the pyrazol-5-ol.
Indeed, other pyrazol-5-ols with either hydrogen atom
or a small alkyl group (i.e., n-propyl) replacing one of
the two benzyl groups did not show any anity at all.
These ®ndings suggested that the 1,4-dibenzyl-pyrazol-
5-ol was the minimum structure necessity for ET receptor
binding anities. Moreover, structural analysis (NMR
and IR),13 revealed that most of these compounds were
in the enol-form (i.e., the pyrazol-5-ol), and not in the
pyrazolone form.
The pyrazole 5-carboxylic acids 37a,b were synthesized
according to the method outlined in Scheme 3.9 The a,g-
diketoester 30 prepared from acetophenone by a litera-
ture method,11 was treated with hydrazine monohydrate
in EtOH at re¯ux to a€ord the corresponding pyrazole
31. Bromination of 31 with NBS in CH2Cl2 yielded the
bromopyrazole 32 which was then alkylated with 3-
methoxybenzyl chloride in the presence of NaH in
DMF at room temperature to give the desired com-
pound 33. Stille coupling of 33 with the corresponding
stannanes 35a,b in the presence of Pd2(dba)3CHCl3-
(dppf) in DMF at 60 ꢀC a€orded the compounds 36a,b.
The requisite stannanes were prepared from the corre-
sponding benzyl chlorides 34a,b with (Bu3Sn)2 in the
presence of Pd(PPh3)4.12 The ®nal pyrazole carboxylic
acids 37a,b were obtained by saponi®cation of 36a,b.
Among the various structural features of the initial
weakly active pyrazol-5-ols, the hydroxy function is the
most likely to give a hydrogen bond or an ionic interac-
tion within the ET receptors. Therefore, it was decided to
investigate its contribution to the binding anities.
Thus, several O-alkylated derivatives of the pyrazol-5-ol
5, which displayed the highest binding anities (IC50s:
1.5 mM/ETA; 11 mM/ETB) in our screening assays, were
synthesized (Table 1). The lack of anities of the O-
methyl analogue 5a highlighted the importance of this
hydroxy group. pKa Measurement in ethanol:water (1:1)
system showed this hydroxy function to be slightly acidic
(pKa=6). More acidic functions were then introduced at
various distances from the pyrazole nucleus. Compound
5c showed improved anities for both ET receptors,
whereas its precursor, ester 5b, did not show any anity
at all. This result indicated that an acid group was
required for potent binding in this region within the ET
receptors. Increasing the length of the spacer between
Results and Discussion
The inhibition of endothelin binding to ETA and ETB
receptors was measured using 125-I labeled ET-1
Scheme 1. Reagents and conditions: (a) (i) NaH/toluene; (ii)
Ar1CH2Cl, Nal and aliquat-336, re¯ux; (b) (i) Ar2CH2NHNH2.HCl,
NaOH (1N); (ii) 2/AcOH, re¯ux; (c) (i) Ar2CH2NHNH2.HCl, NaOH
(1N); (ii) 1/AcOH, re¯ux; (d) Ar1CHO, ZnCl2, toluene, re¯ux; (e) H2,
Pd/C, AcOEt.
Table 2. In vitro endothelin receptor binding anity (IC50 (mM)) for
compounds 5±14
Table 1. In vitro endothelin receptor binding anity (IC50 (mM)) for
compounds 5, 5a±f
No.
R
IC50 (mM)
a
b
ETA
ETB
5
6
7
8
3,4-Methylenedioxy
1.5
98
40
4.3
10
1.3
0.6
48
11
nc
n
No.
R
IC50 (mM)
H
4-F
4-Cl
3,4-diCl
a
b
ETA
ETB
22
5
H
Me
1.5
nc
n
11
n
n
9
8.4
5.4
2.4
39
n
n
5a
5b
5c
5e
5f
10
11
12
13
14
3,4-Methylenedioxy-5-Cl
3,4-Methylenedioxy-6-Cl
4-OMe
CH2COOEt
CH2COOH
(CH2)3COOH
CH2CH2OH
0.45
64
40
2.2
n
>25
3,4-(OMe)2
3,4,5-(OMe)3
n
n
aRat heart ventricles.
bRat cerebellum.
cn=No measurable anity.
aRat heart ventricles.
bRat cerebellum.
cn=No measurable anity.

J. Zhang et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1351±1355
Table 3. In vitro endothelin receptor binding anity (IC50 (mM)) for
compounds 5, 15±23
1353
Scheme 2. Reagents and conditions: (a) K2CO3, DMF, rt, MeI (5a);
BrCH2COOEt (5b); Br(CH2)3COOEt (5d); BrCH2CH2OH (5f); (b)
NaOH (2N), EtOH.
group. Compound 6 with an unsubstituted benzyl
showed very poor anity for ETA and no anity for
ETB subtype. A slightly better anity for ETA receptor
was obtained with a 4-¯uorine atom (7). A similar e€ect
for ETA was observed with a 4-methoxy group, together
with a gain in anity for the ETB receptor (12). How-
ever introduction of additional methoxy substituents
had deleterious e€ects on binding (13, 14). Replacing
the 4-¯uorine substituent by chlorine resulted in a
modest anity for ETB subtype while increasing anity
for ETA receptor by one order of magnitude. Introduc-
tion of a second chlorine at 3-position slightly improved
ETB but not ETA binding. However, the highest a-
nities for both receptors were observed with compounds
5, 10 and 11 which all contain a 3,4-methylenedioxy-
benzyl group (i.e., piperonyl). The most potent derivative
was pyrazol-5-ol 11, which possessed a 3,4-methylene-
dioxy-6-chloro-benzyl group. Interestingly, changing
the 3,4-methylenedioxy for a 3,4-dimethoxy resulted in
a complete loss of anity for both ET receptor subtypes
as already mentioned (5 versus 13). This remarkable
contribution of the 3,4-methylenedioxy substituent to
potency has also been observed by other groups.14 One
possible explanation is the oxygen atoms in the methylene-
dioxy functionality are rigid and well orientated for
binding interaction with ET receptors while those in the
two methoxy groups could not give this kind of inter-
actions, perhaps because of steric e€ects resulting from
the two methyl groups.
No.
R
IC50 (mM)
a
b
ETA
ETB
5
3-OMe
H
2-Cl
3-Cl
2-OMe
4-OMe
1.5
10
11
24
25
14
33
15
16
17
18
19
20
21
22
23
3.8
1.9
1.8
2.1
3.8
1.7
3.5
5.6
9.2
12
2-(OCH2COOH)-4-OMe
3-OH
3-OCH2COOH
3,4-methylenedioxy
36
29
17
aRat heart ventricles.
bRat cerebellum.
Table 4. In vitro endothelin receptor binding anity (IC50 (mM)) for
compounds 5, 24±29
No.
R
IC50 (mM)
a
b
ETA
ETB
5
CF3
CF2CF3
CF2CF2CF3
Me
4-MeO-PhCH2
Ph
4-NO2-Ph
1.5
0.11
0.14
11
24
25
26
27
28
29
3.3
1.0
nc
24
3.2
15
Since the 3,4-methylendioxybenzyl group is such an
important contributor to the binding potency, it was
maintained for the investigation of the second benzyl
moiety (Table 3). IC50 Data examination of these com-
pounds suggested that all substituted benzyl groups
(compounds 5, 16±23) improved the ETA receptor
binding anities by 2 to 6 fold compared to the unsub-
stituted benzyl (15), but had less e€ect on the ETB
receptor binding anities.
20
7.5
0.42
3.1
aRat heart ventricles.
bRat cerebellum.
cn=No measurable anity.
the acid function and the pyrazole nucleus resulted in
decreased potency (5e). The extremely poor anities of
the corresponding alcohol analogue 5f, nearly 100 times
less potent than 5c towards ETA receptor, provided
further evidence for an ionic interaction between the
hydroxy group of these pyrazol-5-ols and the ET
receptors.
All the compounds described above incorporated the
hydrophobic and electron-withdrawing 3-tri¯uoro-
methyl. Therefore, this group could not only contribute
to stabilize the enol-form but also to increase the acidity
of the hydroxy group. In order to de®ne the optimal
structural requirement for the substituent at 3 position
of these pyrazol-5-ol derivatives, several analogues (24±
29) were prepared (Table 4).
As we demonstrated the crucial role of the hydroxy
group, we turned our attention toward the two-benzyl
groups, which also appeared to be important for ET
receptor binding anities as shown by preliminary screen-
ing results. Table 2 summarizes the IC50s of derivatives
with a range of di€erent substituents on the 4-benzyl
Replacement of the CF3 by more hydrophobic penta-
¯uoroethyl (24) or hepta¯uoropropyl (25) of similar
electron-withdrawing potency, improved signi®cantly
both ET receptor binding anities. On the other hand,

1354
J. Zhang et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1351±1355
its replacement by a CH3 group (26) had the opposite
e€ect (IC50s of 25 decreased while those of 26 increased,
both by one order of magnitude). This could be either due
to the low lipophilicity of this methyl or to its electron-
donating e€ect which, in contrast to the CF3 group,
favours the keto- over the enol-form, as con®rmed by
NMR and IR spectra analysis.15 Compound 27 with a
more lipophilic 4-methoxybenzyl group, despite the
predominance of the keto-form, displayed better a-
nities than the methyl analogue 26, but nevertheless
lower anities than compound 5. Compound 28, with a
lipophilic phenyl group which at the same time favours
the enol-form by conjugation e€ect, displayed better
anities than compound 5. Introduction of a nitro
group at the 4-position of this phenyl decreased the
binding anities, probably by repulsive e€ect between
the dipole of the NO2 group and the ET receptors.
These studies clearly indicated, not only the crucial role
of the substituent at the 3 position of the pyrazole ring,
but also the importance of its liphophilic properties.
They also highlighted the in¯uence of their inductive
e€ects on the acidity of the hydroxyl at the 5 position.
Therefore, they con®rmed our initial hypothesis on the
existence of a strong and speci®c ionic interaction
between the hydroxy and the ET receptors.
The pyrazole-5-carboxylic acid 37a displayed 10-fold
improved ETA and nearly 100-fold improved ETB
binding anity compared to the corresponding pyrazol-
5-ol 28. Introduction of the 6-chloropiperonyl, which
was shown to be the best substituent in the pyrazol-5-ol
series, gave the most potent pyrazole-5-carboxylic acid
37b. These encouraging results were in complete agree-
ment with our pharmacophore model obtained from the
SAR studies of the pyrazol-5-ols. Additional results
concerning this novel class of ET antagonists will be
communicated in due course.
Acknowledgements
We would like to thank the Analytical Department
(HMR, Romainville) for performing the spectral analysis.
References and Notes
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(b) NBS, CH2Cl2, rt; (c) 3-MeO-PhCH2Cl, NaH, DMF, rt; (d)
(Bu3Sn)2, Pd(PPh3)4, toluene, re¯ux; (e) Pd2(dba)3CHCl3-(dppf),
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6H), 7.21 (m, 1H); IR (Nujol PE580): 3500±3200 (OH), 1612,
1
1590, 1576, 1492 cm
.
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4.62.78 (dd, 2H), 5.91 (S, 2H), 6.57.88 (m, 6H), 7.16 (t, 1H);
enol-form (II): d 1.99 (s, 3H), 3.55 (s, 2H), 3.76 (s, 3H), 4.82 (s,
2H), 5.89 (s, 2H), 6.57.88 (m, 6H), 7.25 (m, 1H); keto-form (I):
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enol-form (II)=2:1 ; IR (CHCl3): 1698, 1602, 1590, 1504, 1492
1
cm
.