Syntheses and evaluation of quinoline derivatives as novel retinoic acid receptor α antagonists

Article abstract of DOI:10.1016/S0960-894X(01)00177-9

In the course of studies on novel retinoids, we have designed and synthesized a series of quinoline derivatives. One of them, 4-[5-[8-(1-methylethyl)-4-phenyl-2-quinolinyl]-1H-2-pyrrolyl]benzoic acid (12f) shows potent RARα-selective antagonistic activity.

Full text of DOI:10.1016/S0960-894X(01)00177-9

Bioorganic & Medicinal Chemistry Letters 11 (2001) 1215–1218
Syntheses and Evaluation of Quinoline Derivatives as Novel
Retinoic Acid Receptor ꢀ Antagonists
Kouichi Kikuchi,a,* Katsuya Tagami,b Shigeki Hibi,a Hiroyuki Yoshimura,c
Naoki Tokuhara,a Kenji Tai,a Takayuki Hida,d Toshihiko Yamauchia and Mitsuo Nagaia
aDiscovery Research Laboratories, Eisai Co.,Ltd., 1-3, Tokodai 5-chome, Tsukuba-shi, Ibaraki, 300-2635, Japan
bProcess Research Laboratories, Eisai Co., Ltd., 1-3, Tokodai 5-chome, Tsukuba-shi, Ibaraki, 300-2635, Japan
cDevelopment and Technological Services, Eisai Co., Ltd., 4-6-10, Koishikawa, Bunkyo-ku, Tokyo, 112-0002, Japan
dLaboratories of Seeds Finding Technology, Eisai Co., Ltd., 1-3, Tokodai 5-chome, Tsukuba-shi, Ibaraki, 300-2635, Japan
Received 11 December 2000; accepted 10 March 2001
Abstract—In the course of studies on novel retinoids, we have designed and synthesized a series of quinoline derivatives. One of
them, 4-[5-[8-(1-methylethyl)-4-phenyl-2-quinolinyl]-1H-2-pyrrolyl]benzoic acid (12f) shows potent RARa-selective antagonistic
activity. # 2001 Published by Elsevier Science Ltd.
Introduction
In our previous reports concerning a series of novel
retinoids,7 we described that 1 (ER-27191), which has a
3-pyridylmethyl group as a bulky substituent, possesses
potent RAR pan-antagonistic activity.7a Recently, we
reported that 2 (ER-41666), which has a benzopyran
skeleton as a flat structural moiety in the hydrophobic
part and a 2,5-disubstituted pyrrole moiety in the link-
ing part, exhibits moderate RARa-selective agonistic
activity7d (Fig. 1). In the course of our attempts to
introduce a polar heteroaromatic ring into the hydro-
phobic part in order to reduce toxicity,8 we found that
8-isopropylquinoline derivatives show RARa selectiv-
ity, and the introduction of a bulky group at the 4-
position, thereby combining the structural features of
an RAR antagonist (1) and an RARa-selective agonist
(2), generated potent RARa-selective antagonistic
activity. In this paper, we discuss the syntheses and
structure–activity relationship (SAR) of novel quinolyl-
pyrrolyl-benzoic acid derivatives.
Retinoic acid receptors (RARs) are a group of nuclear
receptors belonging to the steroid receptor superfamily.
There are three distinct receptor subtypes (RARa, b,
and g), which possess considerable homology in their
ligand binding domains.1 All-trans retinoic acid
(ATRA) and synthetic analogues of ATRA (retinoids)
have diverse biological activities, including induction of
cellular proliferation, differentiation and death, as well
as developmental changes, through activation of gene
transcription mediated by RARs.2
Although retinoids are thought to have great ther-
apeutic potential, their clinical application is so far lim-
ited3 because of the wide range of toxic effects of
retinoids.4 The diverse actions of retinoids, both desir-
able and undesirable, reflect the existence of multiple
retinoid receptor subtypes. Therefore, subtype-selective
retinoids might have potential therapeutical value. In
particular, RARa-selective antagonists might be effec-
tive in the treatment of airway diseases,5 and they would
also be useful tools to elucidate the mechanisms of reti-
noidal action. Some RARa antagonists have been
reported,6 but more potent compounds would be
desirable.
Chemistry
Aldehydes 5a–f were prepared according to Scheme 1.
2-Isopropylaniline (3) was cyclized with crotonaldehyde
under acidic conditions, followed by oxidation with
SeO2 to afford 5a. Treatment of 3 with dimethyl acet-
ylenedicarboxylate, followed by cyclization gave the
quinolone (6). 4-Substituted aldehydes 5b–f were
synthesized from 6.
*Corresponding author. Tel.:+81-298-47-5861; fax: +81-298-47-
2037; e-mail: k2-kikuchi@hhc.eisai.co.jp
0960-894X/01/$ - see front matter # 2001 Published by Elsevier Science Ltd.
PII: S0960-894X(01)00177-9

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K. Kikuchi et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1215–1218
Chlorination of 6 with POCl3 and PCl5 afforded the ester
(8b). The ester was reduced with DIBAL-H and oxidized
under Swern conditions to afford the aldehyde (5b).
Methylation of 6 with MeI in the presence of K2CO3, fol-
lowed by reduction and oxidation gave the aldehyde (5c).
The quinolone (6) was treated with Tf2O in the presence
of 2,6-lutidine and DMAP to afford the triflate (7). This
was converted to alkyl- or aryl-substituted esters (8d–f)
by palladium-catalyzed cross-coupling with organozinc
reagents or arylboronic acid.9 Transformation of the
esters (8d–f) into the aldehydes (5d–f) was accomplished
by reduction followed by oxidation.
oxidation to gave the enone derivative (9), which was
condensed with methyl 4-formylbenzoate in the pre-
sence of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazo-
lium chloride and triethylamine to afford the 1,4-
diketone (10a).10 Aldehydes 5b–f were condensed with
methyl 4-acryloylbenzoate7c to afford the 1,4-diketones
(10b–f). Treatment of the diketones (10a–f) with
ammonium acetate gave the 2,5-disubstituted pyrrole
derivatives (11a–f), which were hydrolyzed with NaOH
to give the acids (12a–f).
Results and Discussion
Compounds 12a–f were synthesized from the aldehydes
(5a–f) as shown in Schemes 2and 3. Aldehyde 5a was
treated with vinyl Grignard reagent followed by MnO2
The quinoline derivatives (12a–f) synthesized above
were evaluated in vitro for binding affinity towards the
Figure 1.
Scheme 1. (a) Crotonaldehyde, 6 N HCl aq; (b) SeO2, EtOH; (c) (i) dimethyl acetylenedicarboxylate, Triton B, MeOH; (ii) Ph2O, 250 ꢀC; (d) Tf2O,
2,6-lutidine, DMAP, CH2Cl2; (e) PCl5, POCl3; (f) MeI, K2CO3, DMF; (g-d) MeLi, ZnCl2, Pd(PPh3)4, THF; (g-e) EtMgBr, ZnCl2, Pd(PPh3)4, THF;
(g-f) phenylboric acid, Et3N, Pd(PPh3)4, DMF; (h) (i) DIBAL-H, THF; (ii) (COCl)2, DMSO, CH2Cl2 (5b, 5c, 5d); or MnO2, acetone (5e, 5f).
Scheme 2. (a) (i) Vinyl magnesiumbromide, Et2O; (ii) MnO2, CH2Cl2; (b) methyl 4-formylbenzoate, 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium
chloride, Et3N, DMF; (c) AcONH4, MeOH; (d) NaOH aq, EtOH.

K. Kikuchi et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1215–1218
1217
Scheme 3. (a) Methyl 4-acryloylbenzoate, 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride, Et3N, DMF; (b) AcONH4, MeOH; (c) NaOH
aq, EtOH.
Table 1. Competitive binding, transactivation, agonistic activity and antagonistic activity of the quinoline derivatives 12
Compound
Binding affinitya
relative IC50
Subtype-specific transactivatione
HL-60
b
f
relative EC30
Agonistic
activityi
Antagonistic
activityk
No.
R
RARa
RARb
RARg
RARa
RARb
RARg
ED30 (nM)
IC50 (nM)
c
l
12a
12b
12c
12d
12e
12f
H
Cl
MeO
Me
Et
5.7
1.3
0.8
1.7
0.7
1.8
579
79
475
71
32
535
—
3.0
1.9
—
2.8
97
17
38
16
22
5767
1160
4460
903
2500
100
—
l
251
834
141
22
—
1.6
g
j
—
100
l
—
17
j
2.5
g
180
g
—
—
g
j
Ph
432—
—
—
6.4
ATRA
1.0
0.66 (nM)d
1.0
0.52(nM) d
1.0
0.42(nM) d
1.0
1.06 (nM)h
1.0
1.02(nM) h
1.0
0.26 (nM)h
1.5 (nM)
aSpecific binding affinity was defined as the total binding minus the nonspecific binding, and the 50% inhibitory dose (IC50) values were obtained
from logarithmic plots. The selectivity of test compounds for each receptor is indicated as relative IC50, where the IC50 value for each receptor was
divided by that of the natural ligand (ATRA).
bMean of IC50/ATRA IC50
.
cNot detectable (relative IC50>1000).
dMean of ATRA IC50 (nM).
eEC30 values were determined from full dose–response curves ranging from 0.1 nM to 3 mM. Retinoid activity is expressed in terms of relative EC30
which is the concentration of retinoid required to produce 30% of the maximal observed response, normalized relative to that of ATRA.
,
fMean of EC30/ATRA EC30
.
gNot detectable (EC30>3000 nM).
hMean of ATRA EC30 (nM).
iAgonistic activity was evaluated by HL-60 cell differentiation activity.
jNot detectable (ED30>10,000 nM).
kAntagonistic activity was evaluated in terms of inhibition of the HL-60 cell differentiation by ATRA (10 nM).
individual RARs and activity to induce gene transcrip-
tion in a co-transaction assay, according to previous
reports.7c HL-60 differentiation activity was measured
using CD11b as a marker of differentiation, and antag-
onism was evaluated in terms of the ability to inhibit the
differentiation of HL-60 cells induced by ATRA
(10 nM).7a The results are summarized in Tables 1 and 2.
Table 2. Antagonistic activity on subtype-specific transactivation
assay7g (compound 12f)
Compound
Antagonistic activitya IC50 (nM)
RARa
31.2—
RARb
RARg
b
b
12f
—
aAntagonistic activity was evaluated in terms of inhibition of transac-
tivation by ATRA (50 nM).
Compound 12a showed weak affinity for RARa recep-
tor, compared with ATRA. Introduction of a sub-
stituent at the 4-position in quinoline increased the
binding affinity to RARa receptor. Compound 12b,
which has chlorine at the 4-position in quinoline, pos-
sessed moderate affinity to RARa, but showed only
weak cell differentiation-inducing activity on HL-60
cells. Compound 12d, which has a methyl group,
showed similar subtype selectivity and cell differentia-
tion activity to 12b. Introduction of an ethyl group
(compound 12e) caused lower RARa selectivity and loss
of cell differentiation-inducing activity. Moreover,
bNot detectable (IC50>3000 nM).
compound 12e showed partial antagonistic activity.
These findings suggested that the size of the substituent
at the 4-position was a critical factor for RARa agonis-
tic or antagonistic activity in HL-60 cell assay. Com-
pound 12c possessed potent antagonistic activity against
cell differentiation but had weak activity for RARb trans-
activation. Compound 12f, which has a phenyl group as a
bulkier substituent, showed potent antagonistic activity

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K. Kikuchi et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1215–1218
on cell differentiation, and possessed selective affinity
for RARa receptor. Furthermore, 12f did not have
transactivation activity for any receptor subtype, and it
showed RARa-selective antagonistic activity.
Levin, A. A.; Shapio, S. S. In The Retinoids; Sporn, M. B.,
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son, M. I. Toxicol. Appl. Pharmacol. 1990, 103, 324.
In conclusion, novel benzoic acid derivatives which have
an 8-isopropylquinoline moiety in the hydrophobic part
and 2,5-disubstituted pyrrole moiety in the linking part
possessed RARa selectivity. One of them, 4-[5-[8-(1-
methylethyl)-4-phenyl-2-quinolinyl]-1H-2-pyrrolyl]ben-
zoic acid (12f: ER-50891) showed potent RARa-selec-
tive antagonistic activity. This antagonist could be
useful in studies of the role of the RARa receptor in the
action of retinoids, and might be a useful lead compound
for drugs to treat diseases caused by RARa-mediated
gene transactivation.
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