Discovery of 3-Substituted 1H-Indole-2-carboxylic Acid Derivatives as a Novel Class of CysLT1 Selective Antagonists

Article abstract of DOI:10.1021/acsmedchemlett.5b00482

The indole derivative, 3-((E)-3-((3-((E)-2-(7-chloroquinolin-2yl)vinyl)phenyl)amino)-3-oxoprop-1-en-1-yl)-7-methoxy-1H-indole-2-carboxylic acid (17k), was identified as a novel and highly potent and selective CysLT₁ antagonist with IC₅₀ values of 0.0059 ± 0.0011 and 15 ± 4 μM for CysLT₁ and CysLT₂, respectively.

Full text of DOI:10.1021/acsmedchemlett.5b00482

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Letter
Discovery of 3-substituted 1H-indole-2-carboxylic Acid De-
rivatives as a Novel Class of CysLT1 Selective Antagonists
Hua-Yan Chen, Hui Yang, Zhi-Long Wang, Xin Xie, and Fa-Jun Nan
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.5b00482 • Publication Date (Web): 22 Jan 2016
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Discovery of 3-substituted 1H-indole-2-carboxylic Acid Deriv-
atives as a Novel Class of CysLT1 Selective Antagonists
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Huayan Chen,†,b Hui Yang,#, b Zhilong Wang,# Xin Xie,#,* Fajun Nan†,*
† State Key Laboratory of Drug Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, Shanghai, 201203, China
#CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, Shanghai 201203, China
bThese authors contributed equally.
KEYWORDS: Cysteinyl leukotrienes, CysLT1, CysLT2, selective antagonists, asthma
ABSTRACT:
The
indole
derivative,
3ꢀ((E)ꢀ3ꢀ((3ꢀ((E)ꢀ2ꢀ(7ꢀchloroquinolinꢀ
2yl)vinyl)phenyl)amino)ꢀ3ꢀoxopropꢀ1ꢀenꢀ1ꢀyl)ꢀ1Hꢀindoleꢀ2ꢀcarboxylic acid (17k), was
identified as a novel and highly potent and selective CysLT1 antagonist withIC50 values
of 0.0059 ± 0.0011 ꢁM and 15 ± 4 ꢁM for CysLT1 and CysLT2, respectively.
Cysteinylꢀleukotrienes (CysLTs) are potent inflammatory
lipid mediators synthesized from arachidonic acid.1,2 CysLTs
include leukotriene C4 (LTC4), leukotriene D4 (LTD4), and
leukotriene E4 (LTE4). They play established or evolving roles
in asthma, allergic rhinitis, and other inflammatory conditions,
such as cardiovascular diseases, cancer, and atopic dermatitis.3
CysLT2 are less well defined, and there is no specific antagoꢀ
nist being marketed as a therapeutic agent so far.6 Wunder et
al. reported the identification of the first potent and selective
CysLT2 antagonist, HAMI3379 (Figure 2), which was shown
to inhibit the cardiovascular effects mainly through mediation
of CysLT2 receptors.8 Meanwhile, a highly similar compound,
BayCysLT2 (Figure 2), was also reported to be a potent and
selective CysLT2 antagonist.9
4
CysLTs activate at least 2 receptors, designated as CysLT1
and CysLT2,5 which belong to the G proteinꢀcoupled receptor
(GPCR) superfamily.
CysLT1 receptors are mainly expressed in the lung, periphꢀ
eral blood leukocytes and the spleen.4 Most of the pathophysiꢀ
ological effects of CysLTs in asthma are mediated by the
CysLT1 receptor.6 Several CysLT1 selective antagonists have
been launched for treating bronchial asthma and allergic rhiniꢀ
tis, such as montelukast, pranlukast and zafirlukast (Figure 1).6
Figure 2. Selective CysLT receptor antagonists.
Although the marketed CysLT1 selective antagonists are efꢀ
fective therapeutics for the general treatment of mild to modꢀ
erate bronchial asthma, it is known that the current CysLT1
antagonists do not have sufficient effects for some nonresponꢀ
sive patients. A recent report demonstrated that CysLT1 may
also play a role in multiple sclerosis; blocking this receptor
protects the integrity of the bloodꢀbrain barrier and reduces
infiltration of pathogenic T cells into the central nervous sysꢀ
tem.10 More recently, Ludwig et al reported that antiꢀasthmatic
drug montelukast, which antagonizes CysLT1, reduces neuꢀ
roinflammation, promotes hippocampal neurogenesis and imꢀ
proves learning and memory in old animals.11 Therefore, the
development of new CysLT antagonists is still of great interꢀ
est.
Figure 1. LTD4 and launched drugs selective targeting CysLT1
CysLT2 receptors are highly expressed in the peripheral
blood leukocytes, spleen and lymph nodes and are uniquely
expressed in the heart, brain and adrenal glands.5 Recently,
Sekioka, T. et al. reported the expression of CysLT2 receptors
in asthmatic lungs and investigated their possible role in bronꢀ
choconstriction.7 However, the pharmacological roles of
A highꢀthroughput screening (HTS) campaign of our comꢀ
pound library yielded indole derivative 1, which showed miꢀ
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cromolar CysLT1 antagonist activity with an IC50 value of 0.66
Table 1. Effects of Ester Groups on Activity Profiles
1
2
3
4
5
6
7
8
±0.19 ꢁM and exhibited no CysLT2 antagonist activity (Figꢀ
ure 2). Compound 1 shares same hydrophobic (E)ꢀ3ꢀ(2ꢀ(7ꢀ
chloroquinolinꢀ2ꢀyl)vinyl)phenyl group as montelukast, but it
has a unique and essential indoleꢀ2ꢀcarboxylic acid moiety,
which is different from the corresponding counterparts of
known CysLT1 antagonists. The structural novelty of comꢀ
pound 1 encouraged us to further optimize and develop more
potent CysLT1 antagonists.
IC50(ꢁM)a
Cmpd
R1
CysL1
CysLT2
First, we investigated the effects of the ester groups and deꢀ
signed compounds 10aꢀ10j. The syntheses of compounds 10aꢀ
10j are described in Scheme 1. Ethylꢀ4,6ꢀdichloroꢀ1Hꢀindoleꢀ
2ꢀcarboxylate 4 was prepared from 3,5ꢀdichloroaniline in a
twoꢀstep synthetic procedure using a JappꢀKlingemann conꢀ
densation followed by a Fischer indole (azaꢀCope) ring closure
reaction. VilsmeierꢀHaack formylation of 4 afforded aldehyde
5.12 Subsequent ester hydrolysis of 5 afforded carboxylic acid
6, which upon esterification, afforded 7. Compound 7 was
reacted with tertꢀbutyl(triphenylphosphoranylidene)acetate in
a HornerꢀWadsworthꢀEmmons reaction followed by the
chemoselective deprotection of the tertꢀbutyl ester group,
which yielded the α, βꢀunsaturated acid intermediate 8.13 Esꢀ
terification of 8 generated compounds 9aꢀ9j, which were then
converted to compounds 10aꢀ10j using TBAF in THF.
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>100
1
0.66±0.19
>100
>100
>100
>100
>100
>100
~100
>100
~100
~100
10a
10b
10c
10d
10e
Scheme 1. Syntheses of Compounds 10a-10ja
>100
>100
>100
>100
10f
10g
>100
>100
~100
>100
10h
10i
>100
>100
10j
montelukast
pranlukast
zafirlukast
0.31±0.09
27±6
0.023±0.006 43±5
0.014±0.003 58±3
aAssay protocols are provided in the Supporting Information.
IC50 values were obtained from one experiment with 3 replicates.
aReagents and conditions: (a) DMF, POCl3, DCE, reflux, 7 h;
(b) EtOH, LiOH·H2O, 50 oC, 2 h; (c) 2ꢀ(trimethylsilyl)ethanꢀ1ꢀol,
EDCI, DMAP, DCE, rt, overnight; (d) tertꢀbutyl (triꢀ
phenylphosphoranylidene)acetate, toluene, reflux, overnight; (e)
98% HCOOH, rt, overnight; (f) R1Br, Cs2CO3, DMF or R1OH,
DCC/EDCI, DMAP, DMF; (g) TBAF, THF, rt, 2 h.
Scheme 2. Synthesis of 3a
As shown in Table 1, the results revealed that the (E)ꢀ3ꢀ(2ꢀ
(7ꢀchloroquinolinꢀ2ꢀyl)vinyl)phenyl group was necessary for
the antagonist activity of the compounds; replacing it with
other ester groups eliminated antagonist activity against both
CysLT1 and CysLT2. Therefore, we attempted to modify the
functional groups at other positions of hit compound 1 while
retaining the (E)ꢀ3ꢀ(2ꢀ(7ꢀchloroquinolinꢀ2ꢀyl)vinyl)phenyl
group to increase its antagonist activity against CysLT1.
aReagents and conditions: (a) CuCl, quinoline, microwave, 200
oC, 10 min; (b) malonic acid, pyridine, piperidine, 50 oC , 12 h; (c)
(E)ꢀ2ꢀ(3ꢀ(bromomethyl)styryl)ꢀ7ꢀchloroquinoline, Cs2CO3, DMF,
rt, overnight.
The chlorine atoms in the indole ring of compound 1 were
removed and proposed compound 2 (Table 2) was synthesized
following the previously described method. We removed the
carboxylic acid group of compound 1 and yielded compound
3, which was synthesized following the method shown in
Scheme 2. Decarboxylation of 6 provided aldehyde 11,14
which was subsequently converted to 12 using a Doebner
Knoevenagel modification reaction;15 finally, esterification of
12 provided 3.
In order to replace the ester bond of compound 1 with an
amide bond, we intended to synthesize (E)ꢀ3ꢀ(2ꢀ(7ꢀ
chloroquinolinꢀ2ꢀyl)vinyl)benzylamine, unfortunately, we
failed to obtain the intermediate after several synthetic atꢀ
tempts; considering the easy availability of (E)ꢀ3ꢀ(2ꢀ(7ꢀ
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chloroquinolinꢀ2ꢀyl)vinyl)aniline, compound 17a was preꢀ indole ring on the activity profiles with compounds 17cꢀ17k.
1
2
3
4
5
6
7
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pared (Scheme 3). As shown in Table 2, compounds 2 and 17a
exhibited slightly improved antagonist activities against
CysLT1 compared to hit compound 1, which suggested that
derivatives with no substituents in the indole ring were better
than derivatives with chlorine atoms and that amide bonds
were superior to ester bonds in the internal chain. However,
compound 3, which lacked the indoleꢀ2ꢀcarboxylic acid moieꢀ
ty was approximately 47ꢀfold less potent than hit compound 1;
this demonstrated that the carboxylic acid group at position 2
of the indole ring was necessary. These results further supꢀ
ported the common features of CysLT1 antagonists, namely,
they all contained a lipophilic region which incorporates into
the lipophilic pocket of the CysLT1 receptor and an acidic
moiety modelling the C1ꢀcarboxylic acid of LTD4.16ꢀ18 Furꢀ
The syntheses of 17aꢀ17k, 19b, and 21b are described in
Scheme 3. VilsmeierꢀHaack formylation of 4 and 13bꢀ13k
afforded aldehydes 5 and 14bꢀ14k. The Wittigꢀtype olefinaꢀ
tion of the latter compounds and the subsequent deprotection
of the tertꢀbutyl ester group with TFA afforded compounds
15aꢀ15k. Oxidation of 14b afforded 18b. Reduction of 15b by
catalytic hydrogenation afforded 20b. Condensation of 15aꢀ
15k, 18b, and 20b with (E)ꢀ3ꢀ(2ꢀ(7ꢀchloroquinolinꢀ2ꢀ
yl)vinyl)aniline and subsequent hydrolysis provided comꢀ
pounds 17aꢀ17k, 19b, and 21b, respectively.
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Scheme 3. Syntheses of 17a-17k, 19b, and 21ba
thermore, these results were in accordance with the essential
19
structural elements for CysLT1 receptor ligands.16ꢀ17,
The
activity results of compounds in Table 1 and compound 3
demonstrated that the indole ring, the carboxylic acid function,
and the (E)ꢀ3ꢀ(2ꢀ(7ꢀchloroquinolinꢀ2ꢀyl)vinyl)phenyl group
were the three necessary pharmocophores for the novel series,
the activity results of compounds 2 and 17a revealed that reꢀ
movement of chlorine atoms in the indole ring and replaceꢀ
ment of the ester bond with the amide function were favorable
for improvement of the potency, therefore, compound 17b
(Scheme 3) was suggested based on the structureꢀactivity
relationships (SARs) in the present study. Satisfactorily, 17b
demonstrated significantly better antagonist activity against
CysLT1 than hit compound 1, and its antagonist activity
against CysLT2 remained very low. Subsequently, to explore
the effects of the α, βꢀunsaturated double bond at position 3 of
the indole ring of 17b on activity profiles, 17b was modified
leading to 19b and 21b (Scheme 3). As shown in Table 2, 19b
and 21b were approximately 4 and 6ꢀfold less potent against
CysLT1 than 17b, and they demonstrated stronger antagonist
activities against CysLT2 than 17b, which revealed that the
importance of the α, βꢀunsaturated double bond .
aReagents and conditions: (a) DMF, POCl3, DCE, reflux, 7 h;
(b) tertꢀbutyl (triphenylphosphoranylidene)acetate, toluene, reflux,
overnight; (c) TFA, DCM, rt, 3 h; (d) (E)ꢀ3ꢀ(2ꢀ(7ꢀchloroquinolinꢀ
2ꢀyl)vinyl)aniline, HATU, DIPEA, DMF, rt, overnight; (e) NaOH
aq, EtOH, 50 oC, overnight; (f) 30% H2O2, NaClO2,
NaH2PO4·2H2O, CH3CN, rt, overnight; (g) Pd/C, H2, EtOHꢀTHF,
rt, 7 h.
Finally, we investigated the effects of the substituents of the
Table 2. Activity Profiles of Indole Derivatives
IC50(ꢁM)a
Cmpd
R1
R2
X
Y
CysLT1
CysLT2
4,6ꢀdiCl
ꢀCOOH
ꢀCOOH
H
ꢀCH=CHꢀ
ꢀCH=CHꢀ
ꢀCH=CHꢀ
ꢀCH=CHꢀ
ꢀCH=CHꢀ
ꢀ
ꢀOCH2ꢀ
ꢀOCH2ꢀ
ꢀOCH2ꢀ
ꢀNHꢀ
>100
1
0.66±0.19
0.12±0.02
31±13
H
>100
2
4,6ꢀdiCl
>100
3
4,6ꢀdiCl
ꢀCOOH
ꢀCOOH
ꢀCOOH
ꢀCOOH
>100
17a
17b
19b
21b
0.29±0.14
0.0090±0.0043
0.035±0.005
0.058±0.014
H
H
H
ꢀNHꢀ
58±26
23±1
50±18
ꢀNHꢀ
ꢀCH2CH2ꢀ
ꢀNHꢀ
aAssay protocols are provided in the Supporting Information. IC50 values were obtained from one experiment with 3 replicates.
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As shown in Table 3, the fluorine substituted derivatives were
Page 4 of 6
1
2
3
4
5
6
7
8
more potent than the chlorine substituted derivatives (17d vs
17g and 17h vs 17a (Table 2)); 17c, 17d, 17e, and 17f demonꢀ
strated that substitution at position 4 of the indole ring was the
least favorable. Moreover, the methoxy group substituted deꢀ
rivatives exhibited substitution at position 7 of the indole ring
was the most favorable. Among these derivatives, compounds
17b, 17g, and 17k showed comparable low nanomolar level
potencies against CysLT1, while some derivatives exhibited
weak (17b, 17g and 17k) to no (17j) CysLT2 antagonist activiꢀ
ties.
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Table 3. Effects of the Substituents of the Indole Ring on
Activity Profiles
Figure 3. Selective CysLT1 antagonists inhibit leukocyte chemoꢀ
taxis induced by LTD4. Data are from three independent experiꢀ
ments (means ± SEM). ***p 0.001, versus vehicle control,
##p 0.01, ###p 0.001 versus LTD4 (100 nM) treatment
group (Student t test).
﹤
﹤
﹤
IC50(ꢁM)
Cmpd R1
CysLT1
CysLT2
H
0.0090±0.0043 58±26
17b
17c
17d
17e
17f
17g
17h
17i
In summary, we have discovered a novel class of selective
CysLT1 antagonists. Our results indicated that it is essential
that such antagonists possess (E)ꢀ3ꢀ(2ꢀ(7ꢀchloroquinolinꢀ2ꢀ
yl)vinyl)phenyl and indoleꢀ2ꢀcarboxylic acid moieties for efꢀ
fective CysLT1 antagonist activity. Additionally, α, βꢀ
unsaturated amide moieties at position 3 of the indole rings
were also important factors. The most potent compound (17k,
IC50 value of 0.0059±0.0011 ꢁM (CysLT1)) demonstrated
significantly more potent CysLT1 antagonist activity than the
known selective CysLT1 antagonist, montelukast, both in calꢀ
cium mobilization assay and chemotaxis assay. The further
optimization and development including the pharmacokinetic
profile of the most potent antagonists and their pharmacologiꢀ
cal effects evaluated in relevant animal models are in progress
in our lab.
4ꢀCl
5ꢀCl
6ꢀCl
7ꢀCl
5ꢀF
0.067±0.022
0.017±0.002
0.022±0.002
0.016±0.004
36±13
>100
87±17
>100
0.0078±0.0013 46±20
4,6ꢀdiF
0.038±0.001
76±14
46±7
5ꢀMeO 0.025±0.007
6ꢀMeO 0.012±0.007
>100
17j
17k
7ꢀMeO
0.0059±0.0011 15±4
aAssay protocols are provided in the Supporting Information.
IC50 values were obtained from one experiment with 3 replicates.
CysLTs have been reported to induce chemotactic activity
in eosinophils20 and monocytes21. We previously found that
LTD4 could also induce chemotaxis of splenocytes isolated
from mice with EAE (experimental autoimmune encephaloꢀ
myelitis), an animal model of multiple sclerosis,10 and this
effect could be blocked by montelukast.10 We then tested
compounds 1, 17b, 17g, 17j and 17k with the chemotaxis asꢀ
say. We found that these compounds could also block LTD4ꢀ
induced chemotaxis of leukocytes isolated from the spleen of
EAEꢀmice in a doseꢀdependent manner (Figure 3). Compound
1 exhibited similar activity as montelukast (Figure 3 A and B),
and both compounds displayed ~50% inhibition of chemotaxis
at concentrations of 1 ꢁM. Compounds 17b, 17g, 17k and 17j
showed much better inhibitory effects, and all these comꢀ
pounds displayed ≥50% inhibition at concentrations of 100 nM
(Figure 3C, D, E and F). In particular, compounds 17g and
17k, which displayed best antagonist activity in calcium assay
(Table 3), showed significant inhibition of chemotaxis at 10
nM concentration (Figure 3D and E).
ASSOCIATED CONTENT
Supporting Information
Synthetic procedures, analytic data, procedures for the biological
assays, and NMR spectras of the key compounds (PDF). This
material is available free of charge on the ACS Publications webꢀ
site at DOI: XXX.
AUTHOR INFORMATION
Corresponding Authors
* Address correspondence to Dr. Fajun Nan (fjnan@simm.ac.cn)
or Dr. Xin Xie (xxie@simm.ac.cn), the National Center for Drug
Screening, 189 Guo Shou Jing Rd, Shanghai
Author Contributions
bThese authors (H. C. and H. Y.) contributed equally to this work.
Funding Sources
This work was supported by grants from the Ministry of Science
and Technology of China (2015CB964503), and the National
Natural Science Foundation of China (81425024).
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15. Xu, Y. Y.; Li, S. N.; Yu, G. J.; Hu, Q. H.; Li, H. Q., Discovery
Notes
of novel 4ꢀanilinoquinazoline derivatives as potent inhibitors of
epidermal growth factor receptor with antitumor activity. Bioorg.
Med. Chem. 2013, 21, 6084ꢀ6091.
16. Zwaagstra, M. l. E.; Schoenmakers, S. H. H. F.; Nederkoorn, P.
H. J.; Gelens, E.; Timmerman, H.; Zhang, M.ꢀQ., Development of a
threeꢀdimensional CysLT1 (LTD4) antagonist model with an
incorporated amino acid residue from the receptor. J. Med. Chem.
1998, 41, 1439ꢀ1445.
17. von Sprecher, A.; Beck, A.; Gerspacher, M.; Sallmann, A.;
Anderson, G. P.; Subramanian, N.; Niederhauser, U.; Bray, M. A.,
Strategies in the design of peptidoleukotriene antagonists. J. Lipid
Mediators. 1993, 6, 265ꢀ273.
18. Dong, X.; Wang, L.; Huang, X.; Liu, T.; Wei, E.; Du, L.; Yang,
B.; Hu, Y., Pharmacophore identification, synthesis, and biological
evaluation of carboxylated chalcone derivatives as CysLT1
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19. Zhang, M.ꢀQ.; Zwaagstra, M. E., Structural requirements for
leukotriene CysLT1 receptor ligands. Curr. Med. Chem. 1997, 4, 229ꢀ
246.
20. Fregonese, L.; Silvestri, M.; Sabatini, F.; Rossi, G. A., Cysteinyl
leukotrienes induce human eosinophil locomotion and adhesion
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Clin. Exp. Allergy 2002, 32, 745ꢀ750.
21. Woszczek, G.; Chen, L.ꢀY.; Nagineni, S.; Kern, S.; Barb, J.;
Munson, P. J.; Logun, C.; Danner, R. L.; Shelhamer, J. H.,
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The authors declare no competing financial interest.
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