Biphenylsulfonamide endothelin receptor antagonists. Part 3: Structure-activity relationship of 4′-heterocyclic biphenylsulfonamides

Article abstract of DOI:10.1016/S0960-894X(01)00791-0

A number of 4′-heterocyclic biphenylsulfonamide derivatives, formally derived from BMS-193884 (1) by replacing the oxazole ring with other heterocyclic rings, are potent and selective endothelin A (ET_A) receptor antagonists. Among the analogues examined, the pyrimidine derivative 18 is the most potent (K_i=0.9 nM) and selective for the ET_A receptor, approximately equivalent to 1.

Full text of DOI:10.1016/S0960-894X(01)00791-0

Bioorganic & Medicinal Chemistry Letters 12 (2002) 517–520
Biphenylsulfonamide Endothelin Receptor Antagonists.
Part 3: Structure–Activity Relationship of
40-Heterocyclic Biphenylsulfonamides
Natesan Murugesan,* Zhengxiang Gu, Philip D. Stein,
Steven Spergel, Sharon Bisaha, Eddie C.-K. Liu, Rongan Zhang,
Maria L. Webb, Suzanne Moreland and Joel C. Barrish
Department of Chemistry, Cardiovascular Agents, Bristol-Myers Squibb Pharmaceutical Research Institute,
Princeton, NJ 08543-5400, USA
Received 13 September 2001; accepted 19 November 2001
Abstract—A number of 40-heterocyclic biphenylsulfonamide derivatives, formally derived from BMS-193884 (1) by replacing the
oxazole ring with other heterocyclic rings, are potent and selective endothelin A (ETA) receptor antagonists. Among the analogues
examined, the pyrimidine derivative 18 is the most potent (Ki=0.9 nM) and selective for the ETA receptor, approximately equiva-
lent to 1. # 2002 Bristol-Myers Squibb Company. Published by Elsevier Science Ltd. All rights reserved.
The endothelins (ET-1, ET-2, and ET-3) constitute a
family of highly potent endogenous vasoconstrictor
agents with a wide range of additional biological activ-
ities.1,2 The actions of these 21-amino acid peptides are
mediated through two membrane associated, G-protein
coupled membrane receptors, termed ETA and ETB.3,4
The ETA receptor, which is selective for ET-1, is
expressed predominately in vascular smooth muscle
cells where it mediates vasoconstrictive and proliferative
responses. The isopeptide nonselective ETB receptor
mediates both vasoconstriction or vasodilation depend-
ing on the tissue type. Several ETA and ETB selective as
well as nonselective receptor antagonists with a wide
range of therapeutic potential have been described in
the literature.5,6 A number of these antagonists are cur-
rently being investigated to determine the role of endo-
thelin and its receptors in mediating various
pathophysiologies.7ꢀ9
activity relationship (SAR) studies on these analogues
have shown that the oxazole moiety present in BMS-
193884 was in large part responsible for its ETA selec-
tivity and potency.11 The SARs have also indicated that
substitution on the oxazole ring was not tolerated and
generally led to loss of activity. In order to further
investigate the role of the oxazole group, we have
examined its replacement by various other heterocyclic
rings. We report herein the synthesis and SAR of a ser-
ies of 40-heterocyclic biphenylsulfonamides as potent
and selective ETA antagonists.
In recent articles, our group has described a series of N-
isoxazolyl biphenylsulfonamides, exemplified by the
clinical candidate BMS-193884 (1), as potent and highly
selective ETA antagonists (Fig. 1).10,11 The structure–
*Corresponding author. Fax: +1-609-818-3450; e-mail: natesan.
murugesan@bms.com
Figure 1. Structure of BMS-193884.
0960-894X/02/$ - see front matter # 2002 Bristol-Myers Squibb Company. Published by Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00791-0

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N. Murugesan et al. / Bioorg. Med. Chem. Lett. 12 (2002) 517–520
Scheme 1. Synthesis of compound 18: (a) (Ph3P)4Pd, aq Na2CO3, EtOH/toluene; (b) 6 N aq HCl/EtOH.
Chemistry
rial with our previously reported boronic acid derivative
511 using palladium tetrakistriphenylphosphine as the
catalyst gave the biphenylsulfonamide 6. Removal of
the MEM group was achieved using 6 N aqueous
hydrochloric acid in refluxing ethanol to afford 18.
Compounds 7–15, 17 and 19–22 were prepared by an
analogous sequence to that shown in Scheme 1. The cor-
responding 4-bromophenyl heterocyclic intermediates
The general synthesis of biphenylsulfonamides bearing a
heterocyclic ring at the 40-position is exemplified for the
preparation of 18 in Scheme 1.11 Suzuki-coupling of
the 4-bromophenyl boronic acid 2 with 2-bromopy-
rimidine 3 afforded the 2-(4-bromophenyl)pyrimidine
derivative 4. Subsequent Suzuki-coupling of this mate-
Table 1. Substitution of the 40-position of biphenylsulfonamides with a five-membered ring heterocycle
Compd
R
ETA Ki (nM)
ETA KB (nM)
ETB Ki (nM)
A/B selectivity ratio
13,350
1
1.4
19
18,700
7
5.6
44
66
1600
1400
58
52,000
150,000
120,000
9400
9300
3400
6300
1400
144
8
9
19
10
11
12
13
6.7
270
4
270
39,000
130
75,000
18,750
52
3800
ND
>200,000

N. Murugesan et al. / Bioorg. Med. Chem. Lett. 12 (2002) 517–520
519
Table 2. Substitution of the 40-position of biphenylsulfonamides with a six-membered ring heterocycle
Compd
R
ETA Ki (nM)
ETA KB (nM)
ETB Ki (nM)
A/B selectivity ratio
526
14
38
130
20,000
15
16
17
18
19
2.3
37
99
610a
180
21
6300
30,800
20,000
16,000
22,000
2739
832
3.3
0.9
6.2
6060
17,800
3550
34
20
21
22
25
300
220
700a
ND
ND
130,000
170,000
48,000
5200
566
218
aStandard deviations are less than 10% of the mean values for all of the assays; ND, not determined. KB a=KB apparent.
used were prepared using methods described
previously.12 Compound 16 was prepared from 15 by
oxidation using m-chloroperbenzoic acid.
heterocycles at the 40-position of the pendant aromatic
ring (Table 1). Analogues incorporating either a thia-
zole (7) or an oxadiazole (12) ring at this position were
among the most potent five-membered heterocycles
examined in this study. Both compounds showed no
significant differences in their ETA binding affinity
compared to 1 while the selectivity was maintained.
Analogues incorporating other alternate five-membered
ring heterocycles such as imidazole (8), N-methyl imi-
dazole (9), pyrazole (10) or an isoxazole (11) were all
less potent compared to 1 at the ETA receptor. We pre-
viously showed that an acidic group is not tolerated at
the 40-position of the biphenylsulfonamides.11 The tet-
razole analogue 13 is significantly less active, confirming
our previous results.
Results and Discussion
The endothelin receptor binding assays were performed
using CHO cells stably expressing human ETA or ETB
receptors as previously described.11 ETA functional
assays (inhibition of ET-1 induced contractions in rab-
bit carotid artery rings) were performed as previously
described.11 KB values were obtained from experiments
in which at least three different concentrations of test
compound were studied. Apparent KB values were cal-
culated when only one antagonist concentration was
used. The results are summarized in Tables 1 and 2 and,
for comparative purposes, the binding affinities for 1 are
also included.
Replacement of the oxazole in 1 with a phenyl ring
resulted in the terphenyl derivative 14 (Table 2). This
compound was more than 30-fold less active for the
ETA receptor compared to 1 suggesting a putative
hydrogen bond between the heteroatoms of the 40-het-
erocycle and the receptor. The pyridyl analogues 15 and
The present study commenced with the replacement of
the oxazole moiety in 1 with related five-membered ring

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N. Murugesan et al. / Bioorg. Med. Chem. Lett. 12 (2002) 517–520
17 were equipotent to 1 in their ETA binding affinity
indicating that the hydrogen bond between the hetero-
cycle and the receptor may be accessed from either the
2- or 3-position of the heterocyclic ring. However, both
compounds were less potent than 1 in their ETA func-
tional activity. Interestingly, the pyridine N-oxide deriv-
ative 16 was 20-fold less potent than the parent
pyridine analogue 15. The 2-pyrimidine analogue 18
exhibited the highest ETA activity among the com-
pounds prepared in this study. It showed subnanomolar
ETA activity (ETA Ki=0.9 nM; ETB Ki=16,000 nM)
and was equipotent to 1 in its potency as well as selec-
tivity. This compound was also equipotent to 1 in the
ETA functional assay (ETA KB=21 nM). The pyrid-
azine derivative (19), the 3-pyrimidine (20) and the 4-
pyrimidine (21) analogues each display reduced binding
affinity at ETA relative to 1. The 3,5-dimethoxy-2-py-
rimidine derivative 22 was more than 200-fold less
potent than the parent pyrimidine analogue 18 suggesting
that substitution of the pyrimidine ring is not tolerated.
This result is in agreement with our previous findings in
the 40-oxazole biphenylsulfonamide series.
References and Notes
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In summary, a number of 40-heterocyclic biphenylsulf-
onamide derivatives incorporating a five- or six-mem-
bered heterocycles were evaluated for their binding
affinity to the ETA and ETB receptors. Several of these,
such as oxadiazoles (12), 2- and 3-pyridyl (15 and 17)
and pyrimidine (18), were found be effective replace-
ments for the oxazole ring in 1. Among the analogues
examined, the pyrimidine analogue 18 was found be a
subnanomolar ETA antagonist and was equipotent to 1
in its potency, selectivity and functional activity.