The design and synthesis of a novel series of indole derived selective ETA antagonists

Article abstract of DOI:10.1016/S0960-894X(01)00660-6

Conformational constraint has been used as the key design element in the identification of a series of potent and selective ET_A antagonists. The most potent antagonist, 32, (ET_A IC₅₀ = 0.55 nM) is 722-fold selective over t

Full text of DOI:10.1016/S0960-894X(01)00660-6

Bioorganic & Medicinal Chemistry Letters 12 (2002) 125–128
The Design and Synthesis of a Novel Series of Indole Derived
Selective ETA Antagonists
David J. Rawson,* Kevin N. Dack, Roger P. Dickinson and Kim James
Department of Discovery Chemistry, Pfizer Central Research, Sandwich, Kent CT13 9NJ, UK
Received 30 April 2001; revised 3 October 2001; accepted 4 October 2001
Abstract—Conformational constraint has been used as the key design element in the identification of a series of potent and selective
ETA antagonists. The most potent antagonist, 32, (ETA IC50=0.55 nM) is 722-fold selective over the ETB receptor, as measured by
binding experiments. # 2002 Elsevier Science Ltd. All rights reserved.
Introduction
rings and an acidic group (see Fig. 1 for representative
examples). L-749,3299 also exhibits these features and is
a potent and moderately selective ETA antagonist. In-
house modelling studies indicated that conformational
constraint could be used to ‘lock’ the relative positions
of the presumed pharmacophoric groups of L-749,329
in the lowest energy conformation with the benzylic
proton (HB) adopting a position almost coplanar with
the benzoate ring, minimising peri interactions with HA
(Fig. 2).
Since the discovery of the potent vasoconstrictor endo-
thelin-1 (ET-1) in the laboratories of Yanagisawa over
10 years ago,1 this 21 amino acid peptide has been the
focus of intense scientific interest. Three distinct ET
isoforms, ET-1, ET-2 and ET-3, have been discovered
which exert their biological effect through at least two
G-protein coupled receptors, ETA and ETB.2 Elevated
levels of endothelins have been associated with many
disease states including congestive heart failure,3 pul-
monary hypertension,4 chronic renal failure5 and
angina,6 and antagonism of one or both of the ET
receptors represents an attractive target for disease
management. A large number of non-peptide ET
antagonists of different subtype selectivity have been
described in the literature and used as pharmacological
tools to further increase our understanding of the
physiological importance of ET.7 Many have entered
clinical development although, despite the immense
potential of ET antagonists in the clinic, we still await
the first marketed drug in the area. This paper discusses
the design, synthesis and optimisation of a series of
potent and selective ETA antagonists.
Several five- and six-membered rings were explored to
provide a scaffold to put the key groups in the correct
relative positions, and antagonist activity was measured
Design and Synthesis
Many ET antagonists exhibit the common structural fea-
tures8 of three substituted aromatic (or heteroaromatic)
*Corresponding author. Fax:+44-1304-651817; e-mail: david_rawson@
sandwich.pfizer.com
Figure 1.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00660-6

126
D. J. Rawson et al. / Bioorg. Med. Chem. Lett. 12 (2002) 125–128
4-isopropylphenylsulphonamide in the presence of a
strong base furnished the acylsulphonamide 7. This was
converted to 8 and 9 through hydrolysis and amine
coupling, respectively (Scheme 1).
A more versatile route, avoiding the capricious selective
ester hydrolysis, was subsequently developed where the
6-bromoindole 5 was coupled directly with 2-(1,3-ben-
zodioxol-5-yl)-2-bromoacetate (11) to yield 12 (Scheme 2).
Following acylsulphonamide formation (using the con-
ditions already described) the bromide could be func-
tionalised using standard coupling methodologies (e.g.,
palladium mediated carbonylation, Stille, Heck and
Suzuki couplings).
Examples from Table 1 with R2=Et or H were synthe-
sised using the strategy outlined in Scheme 1 using the
appropriate indole N-substituent. Examples 17, 18, 20,
21 and 22 were prepared from 6-bromo-1-ethylindole
using the method used to prepare 7, 8 and 9. Examples
14 and 16 were derived from 6-cyano1-methylindole
using the methodology described in Scheme 1 (Scheme
3) and examples 10 and 15 were prepared by lithium
aluminium hydride reduction of examples 7 and 14,
respectively.
Figure 2.
against cloned human ETA receptor. The 3-substituted
indole (3) proved to be the best template to develop
SAR further. The synthetic strategy adopted, using an
appropriately N-alkylated 6-bromoindole as starting
material, allowed us to rapidly explore SAR on the
indole A-ring. The bromine atom of 5 could be trans-
formed into a methyl ester by halogen–metal exchange
followed by quenching of the resulting lithio inter-
mediate into a THF solution of methylchloroformate.
Coupling with methyl 2-(1,3-benzodioxol-5-yl)-2-bromo-
acetate proceeded smoothly and selective ester hydro-
lysis of the alkyl ester in the presence of the benzoate
ester gave 6. Activation of the acid and coupling with
Results
Binding affinities were determined by competition bind-
ing with 125I-labelled ET-1 for both human cloned ETA
(hcETA) and ETB (hcETB) receptors.10
Once we had discovered the utility of the indole tem-
plate, our initial work focused on optimisation of the
Scheme 1. Reagents and conditions: (a) NaH, MeI, DMF, 25 ꢀC; (b) sBuLi, Et2O, ꢁ78 ꢀC; (c) methyl chloroformate, Et2O, ꢁ78 ꢀC–20 ꢀC; (d)
methyl 2-(1,3-benzodioxol-5-yl)-2-bromoacetate, 2,6-dimethylpyridine, DMF, 80 ꢀC, 8 h; (e) NaOH, 3:1 MeOH/1,4-dioxan, reflux, 1 h; (f) N,N0-car-
bonyldiimidazole, CH2Cl2, reflux, 12 h; (g) 1,8-Diazabicyclo[5.4.0.]undec-7-ene, isopropylbenzenesulphonamide, CH2Cl2, reflux, 12 h; (h) NaOH,
THF/MeOH, 6 h, reflux; (i) N,N0-carbonyldiimidazole, THF, reflux, 12 h; (j) NH3; (k) LiAlH4, THF.

D. J. Rawson et al. / Bioorg. Med. Chem. Lett. 12 (2002) 125–128
127
indole substitution. We quickly discovered that 6-sub-
stitution was favoured over 5- and 7-substitution
(results not shown), and a carboxyl group as in 8 was
favoured over methyl ester (7) or cyano (14), although
the compound was significantly less potent than 1. N-
Alkylation had little effect on potency (compare 8, 18
and 19), and no benefit was achieved by relacement of
the carboxyl at the indole 6-position with tetrazole (16),
hydroxymethyl (10) or aminomethyl (15). However,
potency equivalent to that of 1 was obtained by repla-
cement with a carboxamide group as in 9 and 20. Suc-
cessive alkylation of the amide in 20 to give 21 and 22
was detrimental. Although compounds were ETA selec-
tive, ETA/ETB selectivity was generally modest (Table 1)
and this prompted the second phase of study.
Scheme 2. Reagents and conditions: (a) 2,6-dimethylpyridine, DMF,
80 ꢀC, 8 h.
Scheme 3. Reagents and conditions: (a) CuCN, N-methylpyrrolidine, 150 ꢀC, 48 h; (b) LiAlH4, THF; (c) TMSN3, Bu2SnO, toluene, reflux, 14 h.
Table 1. In vitro endothelin receptor binding affinity (IC50 (nM))
Compd
R1
R2
hcETA IC50 (nM)
hcETB IC50 (nM)
Ratio ETA/ETB
1 (L-749,329)
7
8
—
CO2Me
CO2H
CONH2
CH2OH
CN
—
0.8a
100
22
2.3
19
16a
NDb
1500
34
450
ND
204
—
—
68.2
14.8
23.7
—
Me
Me
Me
Me
Me
Me
9
10
14
15
61
38
CH2NH2
5.4
16
Me
35
ND
—
17
18
19
20
21
22
CO2Me
CO2H
CO2H
CONH2
CONHMe
CONMe2
Et
Et
H
Et
Et
Et
210
32
31
3.5
30
72
ND
2200
ND
68
210
474
—
68.8
—
19.7
7
6.6
aMerck binding data.
bNot determined.

128
D. J. Rawson et al. / Bioorg. Med. Chem. Lett. 12 (2002) 125–128
Table 2. In vitro endothelin receptor binding affinity (IC50 (nM))
Compd
R1
R2
R3
hcETA IC50 (nM)
hcETB IC50 (nM)
Selectivity ETA/ETB
9
iPr
H
Me
Cl
CF3
OMe
H
H
H
Me
Me
H
H
H
H
H
C(O)NH2
C(O)NH2
C(O)NH2
C(O)NH2
C(O)NH2
C(O)NH2
C(O)NH2
C(O)NH2
C(O)NH2
C(O)NH2
C(O)NH2
2.3
12
34
2,570
774
1,100
228
94
1,056
310
846
302
397
15
184
430
146
35
34
203
62
23
24
25
26
27
28
29
30
31
32
1.8
7.5
6.5
2.8
5.2
5.0
3.1
1.1
0.55
H
Me
OMe
CO2H
OMe
OEt
272
275
722
References and Notes
Using the most potent analogue (9) from Table 1 as a
starting point, the effect of modification of substitution
in the sulphonamide ring on ETA/ETB selectivity was
explored using the methodology described in Scheme 1,
steps (f) and (g). The ETA/ETB selectivity proved very
sensitive to aryl sulphonamide substitution (Table 2)
with 4-methyl favoured for both potency and selectivity
(24). Larger substituents, such as OMe and iPr, were less
selective (9 and 27). 2-Substitution with either Me or
OMe (28 and 29) resulted in small increases in ETA
affinity compared to the unsubstituted phenyl group
(23). The combination of 4-methyl and 2-alkoxy, espe-
cially ethoxy, gave excellent levels of both potency and
selectivity (31 and 32). The SAR generated at the sul-
phonamide and indole rings proved to be additive and
we were able to tune the absorption and in vivo profile
of our antagonists by combining the 2 SARs (a paper
describing these studies will be published separately).
1. Yanagisawa, M.; Kurihra, H.; Kimura, S.; Tomobe, Y.;
Kobayashi, M.; Mitsui, Y.; Yazaki, Y.; Goto, K.; Masaki, T.
Nature (London) 1988, 332, 411.
2. (a) Arai, H.; Hori, S.; Aramori, I.; Ohkubo, H.; Nakanishi,
S. Nature (London,) 1990, 348, 730. (b) Sakurai, T.; Yanagi-
sawa, M.; Takuwa, Y.; Miyazaki, H.; Kimura, S.; Goto, K.;
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7. For a recent review on Endothelin Antagonists see:
Benigni, A.; Remuzzi, G. Lancet 1999, 133.
In summary, we have used conformational constraint to
design a novel series of endothelin antagonists. By
appropriate substitution at the indole 6-position and on
the benzenesulphonamide ring, compounds with excellent
potency and selectivity have been identified.
8. For further examples of antagonists sharing these pharma-
cophoric features, see: Bunker, A. M.; Edmunds, J. J.; Berry-
man, K. A.; Walker, D. M.; Flynn, M. A.; Welch, K. M.;
Doherty, A. M. Biorg. Med. Chem. Lett. 1996, 6, 1061. Elliot,
J. D.; Lago, M. A.; Cousins, R. D.; Gao, A.; Leber, J. D.;
Erhard, K. F.; Nambi, P.; Elshourbagy, N. A.; Kumar, C. J.
Med. Chem. 1996, 37, 1553.
9. Walsh, T. F.; Fitch, K. J.; Williams, D. L., Jr.; Murphy,
K. L.; Nolan, N. A.; Pettibone, D. J.; Chang, R. S. L.;
O’Malley, S. S.; Clineschmidt, B. V.; Verber, D. F.; Greenlee,
W. J. Biorg. Med. Chem. Lett. 1995, 5, 1155.
10. Initial work was carried out in the racemic series and the
data presented is from this series. Several antagonists were
separated by chiral HPLC using a ChiralpakTM column.
Details of the synthesis of optically pure indole antagonists of
this class will be published elsewhere.
Acknowledgements
The authors wish to thank D. Ellis, M. Sproates, V.
Sethi, K. Mills, S. Planken, K. Malloy, P. Bradley and
M. Closier for their assistance in preparing the com-
pounds and C. Long, K. Holmes and J. Wakerell for the
in vitro screening of these compounds.