Synthesis and pharmacological activity of 1,3,6-trisubstituted-4-oxo-1,4- dihydroquinoline-2-carboxylic acids as selective ETA antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.08.074

A series of 1,3,6-trisubsituted-4-oxo-1,4-dihyroquinoline-2-carboxylic acid analogs (2a-m) were designed and synthesized and their pharmacological activity determined, with the objective to better understand their SAR as potential ET_A selective inhibitors. Most of the compounds displayed significant ET_A antagonist activity having IC₅₀ for inhibition of binding of the [¹²⁵I]ET-1 to ET_A receptor <10 nM, with good selectivity for ET_A antagonism over ET_B receptor. Based on the in vitro results, SAR of this series of compounds requires an alkoxy substituent at the 6-position to be a straight and saturated chain up to three carbons long, since substitution of unsaturated and branched alkyloxy groups results in decrease in ET_A antagonist activity. In this series, compound 2c (6-O-n-propyl analog) was found to be most potent (IC ₅₀ = 0.11 nM) with ET_B/ET_A selectivity of 8303.

Full text of DOI:10.1016/j.bmcl.2010.08.074

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6840–6844
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and pharmacological activity of 1,3,6-trisubstituted-4-oxo-
1,4-dihydroquinoline-2-carboxylic acids as selective ETA antagonists
Hardik J. Patel a, , Nicole Olgun a, István Lengyel b, Sandra Reznik a, Ralph A. Stephani a,b,
⇑
a Department of Pharmaceutical Sciences, St. John’s University, 8000 Utopia Parkway, Jamaica, NY 11439, USA
b Department of Chemistry, St. John’s University, 8000 Utopia Parkway, Jamaica, NY 11439, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2010
Accepted 16 August 2010
A
series of 1,3,6-trisubsituted-4-oxo-1,4-dihyroquinoline-2-carboxylic acid analogs (2a–m) were
designed and synthesized and their pharmacological activity determined, with the objective to better
understand their SAR as potential ETA selective inhibitors. Most of the compounds displayed significant
ETA antagonist activity having IC50 for inhibition of binding of the [125I]ET-1 to ETA receptor <10 nM, with
good selectivity for ETA antagonism over ETB receptor. Based on the in vitro results, SAR of this series of
compounds requires an alkoxy substituent at the 6-position to be a straight and saturated chain up to
three carbons long, since substitution of unsaturated and branched alkyloxy groups results in decrease
in ETA antagonist activity. In this series, compound 2c (6-O-n-propyl analog) was found to be most potent
(IC50 = 0.11 nM) with ETB/ETA selectivity of 8303.
Keywords:
Endothelin
ETA antagonists
ETAR selectivity versus ETBR
4-Oxo-1,4-dihydroquinoline-2-carboxylic
acids
Ó 2010 Elsevier Ltd. All rights reserved.
Endothelins are divided into three structurally similar subtypes:
endothelin-1, 2, and 3 (ET-1, ET-2, and ET-3), which are members
of 21 amino acid peptide families.1 Among them, ET-1 is the major
isoform involved in human cardiovascular and non-cardiovascular
physiology and pathophysiology. ET-1 is a very potent vasocon-
strictor, 10 times more potent than angiotensin II and 100 times
more potent than epinephrine and also has inotropic, pro-inflam-
matory, and mitogenic properties. It also influences the salt-water
homeostasis, and stimulates the renin–angiotensin–aldosterone
and sympathetic nervous systems.2,3 Increased level of the plasma
concentration of ET-1 has been implicated in several diseases such
as hypertension, pulmonary hypertension, acute myocardial
infarction, congestive heart failure, renal failure, atherosclerosis,
pulmonary fibrosis, and cancer.4
ET-1 exerts its physiological action by binding to the specific
receptors called endothelin receptor type A (ETA) and B (ETB),
belonging to the heptahelical G-protein-coupled receptor super-
family.5 Endothelin receptors are widely expressed in most of the
physiological systems, and interaction of ETA expressed on VSMC
with ET-1 results in vasoconstriction and cell proliferation.6 On
the other hand, ETB activation is mainly responsible for vasodila-
tion depending on tissue location7 and clearance of endogenous
endothelins.8
peutics in clinical development for various diseases like pulmonary
arterial hypertension, chronic heart failure, vascular remodeling
(restenosis, atherosclerosis), renal failure, cancer, and lung fibro-
sis.9 Though theoretically it seems, selective ETA receptor antago-
nists would be useful as therapeutic agents for the treatment of
the aforementioned chronic pathological conditions. Advantages
of a selective antagonist of the ETA receptor10 are:
ꢀ Vasoconstriction in the human cardiovascular system by ET-1
appears to be predominantly mediated by the ETA receptor.
ꢀ The mitogenic and pro-inflammatory effects induced by ET-1 are
mediated by ETA receptor stimulation.
ꢀ Blockade of the ETB receptor would prevent the putative benefi-
cial effects like vasodilation of ET-1-induced NO and PGI2 release
from the endothelium.
ꢀ Since the ETB receptor in the lung is involved in clearance of ET-
1, ETB-antagonism will reduce the rate of clearance of exogenous
ET-1 from the circulation.
Most non-peptidic endothelin receptor antagonists have the fol-
lowing common structural features: a carboxylic acid group or an
acidic sulfonamide moiety between two aromatic or hetero-aro-
matic ring systems (Fig. 1).10 These pharmacophore groups are
positioned so that they mimic amino acids of the ET-1 C-terminal,
which is in a helical form. Different central core units like
indane (enrasentan),11 chromene,12 cyclopentenopyridine (L-
753037),13,14 and pyrrolidine (atrasentan)15 have been incorpo-
rated into endothelin antagonists currently in the clinical trials
(Fig. 2).
Endothelin receptor antagonists (ERAs), both selective ETA
antagonist and non-selective ETA/ETB antagonists, are novel thera-
⇑
Corresponding author. Tel.: +1 718 990 5215; fax: +1 718 990 1876.
E-mail address: stephanr@stjohns.edu (R.A. Stephani).
Present address: Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.08.074

H. J. Patel et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6840–6844
6841
COOH
COOH
O
O
5
8
RO
6
3
2
4
7
N
COOH
N
COOH
1
O
O
O
O
1
2
R = COOH
ETA 0.69nM
ETB 571nM
ETB/ETA 827
R = alkyl, hydroxyalkyl groups
to increase ETA selectivity ?
Figure 3. Hypothesis for the synthesis of 1,3,6-trisubstituted-4-oxo-1,4-dihydro-
quinoline-2-carboxylic acid as selective ETA antagonists.
the quinolone. As shown in Scheme 1, nitration of 3-hydroxyaceto-
phenone with nitric acid in the presence of acetic acid resulted in
the desired regioisomer 3-hydroxy-6-nitroacetophenone, 4, which
had the reported melting point.17,18 Compound 4 was condensed
with 3-carboxybenzaldehyde to yield E-configuration chalcone 5.
Carboxylic acid 5 was converted into ester 6 by reaction with anhy-
drous ethanol saturated with HCl gas followed by MOM protection
of the hydroxyl group resulting in compound 7. Hydrogenation at
45 psi with PtO2 catalyst for 45 minutes reduced both the nitro
group and the double bond of chalcone 7 to give amine 8.
Figure 1. General structure of endothelin receptor antagonists.10
OCH3
OCH3
H
N
OH
N
O
O
COOH
COOH
For the synthesis of intermediate 6-ethylpiperonal, 11, Scheme 2
was followed. Wolff–Kishner reduction of 3,4-methylenedioxyace-
tophenone (9) resulted in crude product, which was purified by
vacuum-distillation at 130 °C and 27 mm/Hg to yield 63.4% of pure
10. Formylation of 3,4-methylenedioxy ethylbenzene (10) with
O
O
O
O
L-753037
Enrasentan
a,a-dichloromethyl methyl ether as precursor of the formyl group,
OCH3
OCH3
COOH
via alkylation catalyzed by titanium tetrachloride, resulted in 6-
ethylpiperonal (11) in excellent yield.19
Reductive amination of 6-ethylpiperonal, 11 with aromatic
amine 8 was then carried out by using hydride reducing agents
such as sodium cyanoborohydride (NaBH3CN),20 or titanium (IV)
isopropoxide (Ti(OiPr)4)/sodium cyanoborohydride (NaBH3CN),21
or sodium triacetoxyborohydride (NaBH(OAc)3).22 Among these
three methods, reductive amination with NaBH(OAc)3 gave the
best yield of product 12. N-acylation of 12 with ethyl oxalyl chlo-
ride gave an excellent yield of compound 13, which on cyclization
by the hindered base 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) in
ethanol gave MOM-protected-4-quinolone diester 14. Deprotec-
tion of MOM-group under acidic condition resulted in key interme-
diate 15 (Scheme 3).
Alkylation of 15 with various alkyl halides in presence of so-
dium hydride and potassium carbonate led to derivatives with dif-
ferent substituents at the 6-position of the quinolone 16a–k
(Scheme 4). The synthesis of the target compounds (2a–m) was
accomplished by potassium hydroxide treatment of the 4-oxo-
quinoline diesters in moderate yields. The general synthetic
scheme along with the physical properties is described in Supple-
mentary data.
N
O
COOH
N
O
O
O
O
O
Atrasentan
O
S-1255
Figure 2. Examples of endothelin receptor antagonists in clinical trials.
Earlier, when the indane ring of SB-209670 was superimposed
on the quinolone ring, a good overlap was obtained with 1,3-disub-
stituted-2-carboxylic quinolones (1). Preliminary SAR resulted in
compound 1 having potent ETA antagonist activity and was 800
times more selective for ETA.16 Also, it had been reported that
introduction of an alkylamino or alkoxy was beneficial to potency
and selectivity in analogs belonging to indane,11 chromene,12 and
cyclopenteno[1,2b]pyridine13,14 carboxylic acid series. Therefore
it was hypothesized that introducing an alkoxy substituent at the
6th position of the A ring of quinolone would lead to a new series
of compounds with increased potency and selectivity towards ETA
receptor (Fig. 3). This hypothesis was validated by generating the
CoMFA model of endothelin receptor antagonists having IC50 val-
ues between 0.19 and 780 nM, which showed steric groups favor-
able at the 6 position of the quinolone ring.
All compounds listed in Table 1 were evaluated for their ability
to inhibit endothelin-A (ETA) and endothelin-B (ETB) receptors
in vitro. The results are summarized in Table 1. For each com-
pound, eight concentrations were tested in the presence of fixed
concentration of radio-labeled ET-1([125I] ET-1) on green monkey
renal tubular (Vero) cells expressing ETA receptors23 and mem-
brane expressing ETB receptor. Besides thirteen proposed com-
In the synthesis of the target compounds 1,3,6-trisubstituted-4-
oxo-1,4-dihydro-quinoline-2-carboxylic acids (2a–m), compound
15 is the key intermediate. Alkylation of 15 with various alkyl ha-
lides led to analogs with different substituents at the 6-position of
pounds, BQ-123 (selective ETA antagonist) was taken as
a
positive control to validate the method. The IC50 values, which
are the concentrations that reduce the [125I] ET-1 binding to the

6842
H. J. Patel et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6840–6844
O
O
O
HO
COOR
OH
OH
b
a
CH3
CH3
NO2
NO2
5
R = H
4
3
c
6
R = C2H5
d
O
O
O
O
COOC2H5
O
O
COOC2H5
e
NO2
NH2
8
7
Scheme 1. Preparation of intermediate 8. Reagents and conditions: (a) HNO3, glacial CH3COOH, 70 2 °C; (b) 3-carboxybenzaldehyde, 10 N NaOH (3 equiv), CH3OH, reflux;
(c) dry HCl gas, anhydrous C2H5OH; (d) MOMCl, NaH, dry K2CO3, dry DMF; (e) 45 psi H2 gas, PtO2, anhydrous CH3OH.
O
O
O
O
O
O
O
b
H
a
H3C
10
11
9
O
Scheme 2. Synthesis of 6-ethylpiperonal, 11. Reagents and conditions (a) (i) NH2NH2ÁH2O, ethanol, reflux, (ii) KOH, 160 °C; (b) TiCl4,
dichloroethane, 0 °C to rt.
a,a-dichloromethyl methyl ether,
O
O
O
O
COOC2H5
O
O
COOC2H5
NH
NH2
a
O
O
8
+
O
O
O
H
12
11
b
COOC2H5
COOC2H5
COOC2H5
O
O
O
O
N
HO
O
O
O
O
c
d
N
COOC2H5
N
COOC2H5
O
COOC2H5
O
O
O
O
O
13
15
14
Scheme 3. Preparation of intermediate 15. Reagents: (a) NaBH(OAc)3, DCE; (b) ethyl oxalyl chloride, NEt3, dry DMF; (c) DBU, ethanol; (d) dry HCl gas, anhydrous C2H5OH.
receptors by 50%, were determined for each drug and are listed in
Table 1.
two carbons (2b IC50: 6.6 nM), there is a sixfold increase in ETA
antagonist activity and a slight increase in selectivity for ETA over
ETB, i.e., 473 for 2b versus 399 for 2a. Increase in chain length by
one more carbon to 3 carbons (2c) resulted in 60-fold increase in
ETA (IC50: 0.11 nM) and threefold increase in ETB (IC50: 913 nM)
antagonist activity compared to 2b. Although there is increase in
binding affinity for both the receptors, a n-propoxy group at 6-po-
sition of quinoline is more beneficial for ETA receptor binding as
seen in selectivity of more than 8000 for ETA over ETB. There is
10-fold decrease in ETA antagonist activity compared to 2c when
the side chain length is increased by one carbon to butyl (2g;
On the basis of this study, the following structure–activity rela-
tionships are proposed for the 1,3,6-trisubstituted-4-oxo-1,4-dihy-
dro-quinoline-2-carboxylic acid analogs, 2a–m as an ETA
antagonists. Among the compounds tested, 6-O-ethyl (2b), 6-O-n-
propyl (2c), 6-O-n-butyl (2g), 6-O-i-butyl (2h), 6-O-sec-butyl (2i),
6-O-propan-3-ol (2l), 4-oxo-1,4-dihydroquinoline diacids dis-
played significant ETA antagonist activity having IC50 for inhibition
of binding of the [125I]ET-1 to ETA receptor <10 nM. As shown in Ta-
ble 1, when the 6-OH group of 2a is replaced by a 6-alkoxy group of

H. J. Patel et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6840–6844
6843
COOH
COOC2H5
COOC2H5
O
N
O
N
O
N
RO
KOH/ C2H5OH
reflux
RO
HO
R-X / DMF
NaH/K2CO3
COOH
COOC2H5
COOC2H5
O
O
O
O
O
O
2a-m
Target Compounds
14 (R = MOM)
15 (R = H)
16a-k
15
X= Cl, Br, I
R = C2H5, n-C3H7, i--C3H7
n-C4H9, i--C4H9, sec-C4H9
n-C5H11, CH2=CH-CH2,
cyclo -propyl-CH2
OH-CH2CH2CH2, COOH-CH2
Scheme 4. Synthesis of 6-O-substituted-4-oxo-quinoline-dicarboxylic acids (2a–m). Reagents and conditions: (a) alkyl halides, NaH, dry K2CO3, dry DMF; (b) 6 N KOH
(6 equiv), C2H5OH, reflux.
Table 1
In vitro inhibitory binding assay (IC50) of 1,3,6-trisubstituted-4-oxo-1,4-dihydroquinoline-2-carboxylic acids, 2a–m
COOH
O
RO
N
COOH
O
O
2a-m
a
b
No.
R
Mp (°C)
ETA IC50 (nM)
ETB IC50 (nM)
ETB/ETA
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
C2H5
n-C3H7
i-C3H7
CH2@CH–CH2
CH3–O–CH2
n-C4H9
198–199
213–215
162–163
199–200
165–166
176–177
161–162
229–231
185–186
173–174
153–155
192–194
177–180
—
38.9 2.6
6.6 1.1
15561.5 162.7
3119 54.3
913.4 27.2
677 9.6
1131 24.8
1030 17.3
548.2 14.5
1983 35.7
—
399
473
8304
50
30
43
381
315
—
—
—
0.11 0.02
13.5 1.5
38.1 3.6
24.4 2.9
1.44 0.6
6.3 1.5
9.9 1.7
115.9 11.4
610 54
i-C4H9
sec-C4H9
cyclo-C3H5–CH2
n-C5H11
HO–CH2CH2CH2
HOOC–CH2
BQ123
2j
2k
2l
—
—
7.4 0.9
4387 63.7
1453 20.7
—
593
5
—
2m
284.5 3.5
24.8 1.3c (25)
a
b
c
Monkey renal cells CCL-81 grown as monolayer.23 n = 3.
Endothelin-B receptor precursor (human) membranes. n = 2.
Literature IC50 value, ibid.
IC50: 1.6 nM), but still shows better activity than 2b. Further in-
crease in length to 5 carbons (2k; IC50 610 nM) resulted in 6000-
fold loss in activity compared to 6-O-n-propyl analog (2c), also
seen in the cyclopenteno[1,2-b]pyridine series as ETA receptor
antagonist.14
Replacement of the saturated 6-O-n-propyl group with the
unsaturated 6-O-allyl group resulted in 2e analog (IC50 = 38.11 nM)
380 times less active than the n-propyl analog 2c. This suggests
that a saturated alkyl chain is required at the 6-position of the 4-
oxo-1,4-dihydroquinoline diacids for better ETA antagonist activity.
Also, when the second atom of the n-propyl chain in 2c is replaced
by isosteric O (2f; IC50: 24.4 nM), there is 240-fold decrease in
activity compared to 2c.
compared to 2b when the methylene group of the ethyl chain
is substituted, 2d (i-propyl, IC50 = 13.5 nM). Similarly, substitu-
tion of the methylene group at C1 of the 6-O-n-propyl chain re-
sulted in compound 2i (6-O-sec-butyl) which is 90-fold less
active, than 2c, in inhibition of binding of the [125I]ET-1 to ETA
receptor (IC50 = 9.9 nM). Likewise, branching at C2 of the alkyl
chain is not tolerated, as substitution of a methyl group at C2
of the 6-O-n-propyl chain resulted in analog 2h (6-O-i-butyl)
which is 60 times less active as ETA receptor antagonist
(IC50 = 6.6 nM) than 2c. Also, compound 2j (6-O-cyclopropylm-
ethyl) which is a cyclic analog of 2h, shows 1000 times less
ETA receptor antagonist activity than 2c. These results suggest
that straight chain saturated alkoxy groups are required at the
6-position of the 4-oxo-1,4-dihydroquinoline diacids for good
ETA receptor antagonism.
Substitutions at the C1 of the 6-O-alkyl chain are not well tol-
erated. There is a twofold decrease in ETA antagonist activity

6844
H. J. Patel et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6840–6844
Introduction of a hydroxyl group (2l; IC50: 7.4 nM) at C3 of the
Supplementary data
6-O-n-propyl side chain resulted in 70-fold reduction in ETA recep-
tor antagonist activity compared with 2c. Also, substitution of a
carboxylic acid group (2m; IC50: 284.46 nM) for a methyl group
in 2b causes a 43-fold decrease in binding affinity for ETA receptor
compared with 2b. These results are consistent with the previously
reported SAR of cyclopenteno[1,2-b]pyridine analogs as ETA recep-
tor antagonists.14
Compound 2a was found to reduce lung inflammation induced
by lipopolysaccharide (LPS),24 cigarette smoke, and ET-125 in a
hamster animal model by reducing the recruitment of broncoalve-
olar lavage fluid (BALF) leukocytes (neutrophils and macrophages).
Therefore, reducing ET-1 activity with selective ETA receptor antag-
onists could potentially decrease neutrophil derived enzymes and
oxidants in the lung, thereby decreasing or inhibiting the progres-
sion of lung injury. Compound 2a was also effective in controlling
preterm delivery induced by lipopolysaccharide (LPS) in a pregnant
mouse animal model.26 This result, in accordance with previous lit-
erature, suggests the role of ET-1 in both normal parturition and
premature birth.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.08.074.
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The authors thank Maulik Patel for helping to construct a CoM-
FA model. Support for this research was provided by Saint John’s
University.