1,3-disubstituted-2-carboxyl quinolones: Highly potent and selective endothelin A receptor antagonists

Article abstract of DOI:10.1016/S0960-894X(00)00264-X

The design, synthesis, and in vitro biological activity of a series of 2-carboxy quinolone antagonists selective for the endothelin A receptor are presented. Introduction of a second acid group in position 3 of the quinolone ring increases dramatically the selectivity for ET(A). (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00264-X

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1487±1490
1,3-Disubstituted-2-carboxy Quinolones: Highly Potent and
Selective Endothelin A Receptor Antagonists
Jean-Luc Haesslein,a,* Isabelle Baholet,a Michel Fortin,b Alain Iltis,a
Jean Khider,a Anne Marie Periers,a Christine Pierrea 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 7 January 2000; accepted 5 May 2000
AbstractÐThe design, synthesis, and in vitro biological activity of a series of 2-carboxy quinolone antagonists selective for the
endothelin A receptor are presented. Introduction of a second acid group in position 3 of the quinolone ring increases dramatically
the selectivity for ETA. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
AT1 receptor,15 also showed moderate anity for both
ETA and ETB receptors (Fig. 1).
Endothelin 1 (ET-1), a 21 amino-acid peptide, belongs
to a family of highly potent endogenous vasoconstrictor
agents along with ET-2 and ET-3.1 It exerts its action by
interacting with at least two speci®c G protein coupled
receptors, ETA and ETB.2
Struck by the high anity level of SB 209670 (1) for both
ETA and ETB receptors, and by the major contribution
of a methylenedioxyphenyl group and an acid function,
we superimposed the indane ring of SB 209670 with the
quinolone ring. A good overlap could be obtained with
1,3-disubstituted-2-carboxylic quinolones (2) (Fig. 2).
ETA, which is selective for ET-1 and ET-2 over ET-3, is
mainly found in vascular smooth muscle cells (VSMC)
and mediates vasoconstriction3 and VSMC proliferation.4
ETB, which is non-selective for the three isoforms, med-
iates either vasoconstriction or vasorelaxation, depending
on its tissue location.5,6
Herein we describe the synthesis and structure activity
relationships of this series, yielding highly potent and
selective ETA antagonists.
Endothelin has been implicated in a number of human
diseases, including hypertension, congestive heart failure,
acute renal failure, pulmonary hypertension, restenosis,
stroke and cerebral vasospasm.7
Chemistry
As no synthesis of 1,3-disubstituted-2-carboxy quinolones
had been described, we envisaged to create the quinolone
ring by cyclisation of the corresponding oxamate 6. Thus,
o-nitroacetophenone was reacted with the appropriate
aldehyde at room temperature overnight, in the pre-
sence of 2N sodium hydroxide in methanol.16 As few as
0.1 to 0.5 equiv of sodium hydroxide are sucient for the
reaction to occur. For base sensitive aldehydes, the reac-
tion was performed in the presence of a catalytic amount
of piperidine and acetic acid in re¯uxing toluene, yielding
the corresponding chalcones in 80 to 95% yield. Both the
double bond and the nitro group were cleanly reduced
over platinum oxide, giving compound 4 (Scheme 1).
Several peptidic as well as non-peptidic endothelin
antagonists have been reported in the literature, being
either ETA selective (i.e., BQ 123,8 BMS 182874,9 A-
127772,10) ETB selective (BQ 788 11) or non selective
(i.e., PD 142893,12 Bosentan,13 SB 209670 14).
During the course of our screening of G-protein coupled
receptor antagonists, we discovered that 6-substituted
quinolones, which were fairly good antagonists of the
The resulting aminoketones 4 were then submitted to
reductive amination with the corresponding aldehyde
*Corresponding author. Tel.: +33-1-49-91-53-80; fax: +33-1-49-91-
50-87; e-mail: jean-luc.haesslein@aventis.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00264-X

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J.-L. Haesslein et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1487±1490
yielding compounds 5 in 50 to 70% yield. Condensation
of 5 with ethyl oxalyl chloride proceeded smoothly to
give compound 6 quantitatively.
Biological results
All the compounds were tested for their ability to inhibit
125I-ET1 binding to rat ventricle (ETA) or to rat cere-
bellum (ETB).17
The key step of the synthesis was the cyclization of 6
into the corresponding quinolone ring. This could in
fact be achieved in high yield under a variety of condi-
tions (K2CO3, MeOH; DBU, EtOH; EtONa, EtOH;
tBuOK, THF), the two ®rst leading to cleaner reaction
mixtures. Finally, the ester group was saponi®ed with 2
equiv of 6N KOH in EtOH under heating, and the
compounds tested as their potassium salts.
From the results in Table 1, it appears that the position
of the methylenedioxyphenyl group is very important in
this series, 9 being 25 times more potent than 10 both on
ETA and ETB. We then investigated the e€ect of various
substituents on the methylenedioxyphenyl group in R1
(cpds 11a±16); of these, derivatives with a substituent
(Cl, vinyl, Et) next to the methylene group showed the
highest activity, ®ve to ten times more potent than com-
pound 9, giving rise to low nanomolar derivatives. In
addition, all these compounds showed a good selectivity
for ETA, 11a being the most dissociated.
Most of the derivatives showed good aqueous solubility
(>20 mg/mL).
Therefore this group was retained in position 1 of the
quinolone ring and the in¯uence of R2 was investigated
(Table 2).
SeveraltypesofsubstituentswereevaluatedasR2:aromatic
(11c±11k), heteroaromatic (11l±11n) and non-aromatic
(11o±11r).
Figure 1.
Clearly, the deletion of CH2R2 leads to a loss of activity
(11b). All the aromatic analogues tested are in the same
range of activity, except compound 11e, which incorpo-
rates the side chain of SB 209670 and is surprisingly far
less active. The selectivity on ETA which is always good,
increases dramatically through the introduction of an
acid function in 11f making this compound 4000 times
more potent on ETA than on ETB.18
The same phenomena is observed for non-aromatic
compounds: introduction of an acid or an ester (11p,
11q and 11r) function increases the selectivity (>1000).
Figure 2.
However, introduction of an acid function in the meta
position does not lead to such a boosting in selectivity (11i).
Scheme 1. Reagents and conditions: (a) RCHO, 0.1±0.5 equiv 2N NaOH, MeOH or cat. Piper; AcOH, Toluene, re¯ux, 80±95%; (b) H2, PtO2,
EtOAc, 100%; (c) 3,4-methylenedioxybenzaldehyde, NaBH3CN, AcOH, MeOH, 50±70%; (d) ClCOCOOEt, THF, NEt3, rt, 100%; (e) K2CO3,
EtOH or DBU, EtOH, 80±90%; (f) 6N KOH, EtOH, re¯ux, 90%.

J.-L. Haesslein et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1487±1490
Table 1. Endothelin receptor binding anity (nM) Table 2. Endothelin receptor binding anity for compounds 11
1489
Compound
R1
CH2R2
ETA
10.7
ETB
606
Compound
CH2R2
H
ETA
8700
ETB
9
11b
29,000
10
11a
12
255
1.6
16000
216
11c
11d
4.1
157
570
10.9
7.8
244
11e
11f
11g
11h
54.3
4.6
1.9
5.7
549
17,100
789
13
18.9
9.5
187
14
244
15
16
1.8
1
70
69
166
11i
3
500
190
11j
5.6
8.2
20.4
5.7
29
At the receptor level, there is no di€erence in activity or
selectivity while going from the acid to the ester (11i versus
11k, 11q versus 11r). When introducing an acid function,
there is no improvement on ETA activity (11c versus 11f)
but only a strong drop in ETB activity, suggesting a sig-
ni®cant di€erence between ETA and ETB receptor
structure in this region.
11k
11l
747
1603
1890
1900
100
11m
11n
11o
11p
11q
11r
In vivo, compounds of type 11 and 16 gave the best
results in the pithed rat assay19 (ED50=1 mg/kg IV),
therefore the best substituents found in 11 as R2 were
introduced in 16. This led to compound 16i which shows
an ED50 of 0.1mg/kg IV in the pithed rat, together with a
sub-nanomolar anity for ETA. Moreover, this com-
pound is orally active in the ET-1 induced death in
mice20 (ED50=10 mg/kg po).
1.1
93
9500
6630
5000
3.4
4.7
In conclusion, we have found a new series of highly
potent and selective ETA antagonists, which are valuable
tools for further understanding the physiological and
pathophysiological role of endothelin.
Acknowledgements
We would like to thank Analytical Department (HMR,
Romainville) for performing the spectral analysis.

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11. Ishikawa, K.; Ihara, M.; Noguchi, K.; Mase, T.; Mino,
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