Structure-activity relationships of a novel class of endothelin receptor selective antagonists; 6-carboxy-2-isopropylamino-5,7-diarylcyclopenteno[1,2-b] pyridines

Article abstract of DOI:10.1016/j.bmcl.2004.01.008

The synthesis and structure-activity relationships of 6-carboxy-2- isopropylamino-5,7-diarylcyclopenteno[1,2-b]pyridine class of ET_A receptor selective antagonists were described. These derivatives were prepared from the optically active key in

Full text of DOI:10.1016/j.bmcl.2004.01.008

Bioorganic& Medicinal Chemistry Letters 14 (2004) 1503–1507
Structure–activity relationships of a novel class of endothelin
receptor selective antagonists; 6-carboxy-2-isopropylamino-5,7-
diarylcyclopenteno[1,2-b]pyridines
Hirobumi Takahashi, Norikazu Ohtake,* Toshihiro Sakamoto, Tomoharu Iino,
Nobuhiko Kawanishi, Masayuki Nakamura, Takashi Yoshizumi, Kenji Niiyama,
Satoshi Ozaki, Hiromasa Okada, Akiko Kano, Hiroyuki Takahashi, Yasuyuki Ishii,
Megumu Okada, Michiyasu Saito, Yoshio Sawazaki, Takashi Hayama
and Masaru Nishikibe
Banyu Tsukuba Research Institute in collaboration with Merck Research Laboratories, Okubo-3, Tsukuba 300-2611,
Ibaraki, Japan
Received 21 October 2003; accepted 5 January 2004
Abstract—The synthesis and structure–activity relationships of 6-carboxy-2-isopropylamino-5,7-diarylcyclopenteno[1,2-b]pyridine
class of ETA receptor selective antagonists were described. These derivatives were prepared from the optically active key
intermediates (3, 4, 10, and 13). Optimization of the substituent at the 2-position of the bottom 4-methoxyphenyl ring of the lead
compound 1 led to identification of 2-hydroxy-1-methylethoxy (2g and h), hydroxyalkyl (2i, m, and p), 3-methoxy-2-methylpropyl
(2t and u), N-acetyl-N-methylaminomethyl (2v), and 2-(dimethylcarbamoyl)propyl (2w) derivatives that showed greater than 1000-fold
selectivity for the ETA receptor over the ETB receptor with excellent binding affinity (IC50<0.10 nM). Further screening of
these compounds by assessing the plasma exposures at 1 h, 4 h, and 8 h after oral administration (3 or 10 mg/kg) in rats led to
identification of the hydroxymethyl (2i) and 3-methoxy-2-methylpropyl (2u) derivatives exhibiting good oral bioavailability in rats.
# 2004 Elsevier Ltd. All rights reserved.
1. Introduction
tissue beds, it has been linked to vasodilation and the
clearance of endogenous endothelins.3
Endothelins (ET-1, ET-2, and ET-3) were discovered as
highly potent endogenous vasoconstrictor peptides and
are known to possess a variety of additional biological
activities.1 The actions of these endothelins are medi-
ated through two distinct G-protein coupled receptors
(ETA and ETB).2 The ETA receptor is expressed pre-
dominantly in vascular smooth muscle cells and med-
iates vasoconstrictive and proliferative responses. The
ETB receptor is the major receptor on endothelial cells,
but the functions remain to be clearly understood.
While the ETB receptor mediates constriction in some
4
5
A number of ETA and ETB receptor selective as well
as ETA- and ETB-balanced receptor antagonists6 have
been described in the literatures, and these endothelin
receptor antagonists are currently being investigated as
to the roles of endothelins and their receptors in med-
iating various phathophysiology. Previously, we descri-
bed a new class of endothelin receptor antagonists
with a 6-carboxy-2-substitued-5,7-diarylcyclopenteno[1,2-
b]pyridine skeleton, in which the selectivity of com-
pounds for the ETA receptor over the ETB receptor was
depended mainly on the substituent at the 2-position of
the cyclopenteno[1,2-b]pyridine core.7 Particularly, an
isopropylamino moiety at this position was identified as
one of the most effective functional groups in terms of
enhancing the selectivity for the ETA over the ETB
receptor. Our efforts focusing on the optimization of the
* Corresponding author. Tel.: +81-29-877-2000; fax: +81-29-877-
2029; e-mail: ootakenr@banyu.co.jp
0960-894X/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.01.008

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H. Takahashi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1503–1507
substituent at the 2-position of the 4-methoxyphenyl
ring attached at the cyclopenteno[1,2-b]pyridine core
have been made to identify potent and orally bioavail-
able ETA receptor selective antagonists. Herein, we wish
to describe the synthesis and the structure–activity rela-
tionships (SARs) of these cyclopenteno[1,2-b]pyridine
derivatives.
2. Chemistry
Robust syntheticmethods of the novel class of the opti-
cally active 6-carboxy-2-isopropylamino-5-(3,4-methyl-
enedioxyphenyl)-7-(4-methoxy-2-substituted-phenyl)cyclo-
penteno[1,2-b]pyridines (2a–x) via the key intermediates
(3, 4, 10, and 13) have been developed as shown in
Schemes 1–4.8 Synthesis of the 7-(2-alkyloxy-4-methoxy-
phenyl)cyclopenteno[1,2-b]pyridine derivatives (2a–h)
was started from N-oxidation of the pyridine nitrogen
of 3 with m-chloroperbenzoic acid (Scheme 1). The
resulting N-oxide was treated with N-isopropyl-
benzimidoyl chloride in the presence of triethylamine
(NEt3) to produce the migrated product, 2-(N-isopro-
pyl-N-benzoylamino)pyridine 4 in 87% yield.9 Optical
resolution of 4 was achieved by CHIRALPAK AD1 to
produce the optically active 4 in 45% yield. Debenzyla-
tion of 4 followed by alkylation of the resulting phenol
moiety gave 6, which were hydrolyzed with 4N NaOH
to afford the desired derivatives (2a–f) in good yields.
Compound (2g) or (2h) was prepared from the optically
active intermediate 3 by the 8 step reaction sequence, in
which the N-isopropyl-N-benzoylamino moiety at the 2-
position of the cyclopentenopyridine core was intro-
duced after the functionalization of the phenol moiety
(Scheme 2).10
Scheme 1. Synthesis of the 2-alkoxy-4-methoxyphenyl derivatives (2a–f).
Reagents: (a) mCPBA, CHCl3, 0 ꢀC, 87%; (b) PrN=C(Cl)Ph, Et3N,
i
CHCl3, reflux, 87%; (c) CHIRALPAK AD, Hexane–iprOH (7:3),
45%; (d) H2, Pd–C, MeOH, rt, quant.; (e) 60% NaH, iodoalkane,
DMF, rt; (f) 4N NaOH, MeOH, reflux.
Scheme 2. Synthesis of the 2-alkoxy-4-methoxyphenyl derivatives (2g and h). Reagents for 2g: (a) (1) CHIRALPAK AD, Hexane–iPrOH (7:3),
i
42%; (2) H2, Pd–C, THF, rt, quant.; (b) (S)-BrCH(Me)CO2 Bu, K2CO3, Kl, MEK, reflux, 40%; (c) 4N NaOH, MeOH, rt, 92%; (d) BH3–THF
complex, THF, 0 ꢀC to rt, 52%; (e) Ac2O, pyridine, rt, 91%; (f) mCPBA, CHCl3, 0 ꢀC, 60%; (g) iPrN=C(Cl)Ph, CsF, MS3A, (ClCH2)2, reflux, 57%;
(h) 6N NaOH, reflux, 66%.
Scheme 3. Synthesis of the 2-substituted-4-methoxyphenyl derivatives (2i and v). Reagents: (a) (CH2=CH)Bu3Sn, PdCl2(PPh3)2, LiCl, DMF,
110 ꢀC, 92%; (b) OsO4, N-methylmorphine-N-oxide, CH3CN–H2O, rt; (c) NaIO4, THF–H2O, 0 ꢀC; (d) NaBH4, MeOH, 0 ꢀC, 56% for 3 steps; (e)
Ac2O, Et3N, DMAP, CHCl3, rt, 65%; (f) mCPBA, CHCl3, 0 ꢀC; (g) iPrN=C(Cl)Ph, Et3N, CHCl3, reflux, 91% for 2 steps; (h) Optical resolution by
CHIRALPAK AD, Hexane–iPrOH (7:3), 47%; (i) 4N NaOH, MeOH reflux, 88%; (j) 1N NaOH, MeOH, rt, 88%; (k) NaI, TMSCl, CH3CN, then
40% MeNH2, MeOH, rt, 81%; (l) 9-BBN, THF, rt; (m) Ac2O, Et3N, CHCl3, rt, 39% for 2 steps; (n) TFA, rt, 93%.

H. Takahashi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1503–1507
1505
Scheme 4. Synthesis of the 2-substituted-4-methoxyphenyl derivatives via Pd-catalyzed Stille or Heck reaction. Stille reaction: Tin reagent (1.2
equiv), PdCl2(PPh3)2 (5.5 mol%), LiCl (3 equiv), DMF (0.1M), 130 ꢀC. Heck reaction: olefin (5–10 equiv), PdCl2(PPh3)2 (10–20 mol%), NaHCO3 (3
equiv), DMF, 130 ꢀC.
Scheme 3 shows the synthesis of hydroxymethyl (2i) and
N-acetyl-N-methylaminomethyl (2v) derivatives. Stille
coupling of the triflate 10 with tributyl(vinyl)tin in the
presence of lithium chloride provided 11 in 92% yield.11
Transformation of the vinyl moiety to the acetoxy-
methyl group (12) was achieved by the conventional 4
reaction steps; (1) cat. OsO4, N-methylmorphorine-N-
oxide (NMO)/CH3CN–H2O, (2) NaIO4/THF–H2O, (3)
NaBH4/MeOH, (4) Ac2O, NEt3, 4-dimethylaminopyr-
idine (DMAP)/CHCl3. Introduction of the N-isopropyl-
N-benzoylamino moiety into the 2-position of the
cyclopentenopyridine core in 12 and the subsequent
optical resolution produced the optically active inter-
mediate 13. Basichydrolysis of both the benzoylamino
and tert-butyl ester moieties in 13 produced 2i in 88%
yield. With regard to the synthesis of 2v, the acetoxy
group of the optically active 13 was selectively hydro-
lyzed under a mild basiccondition (1N NaOH/MeOH)
to afford the hydroxymethyl derivative 14, which was
converted to the corresponding N-methylaminomethyl
group (15). Selective deprotection of the benzoyl group
by treatment with 9-BBN12 followed by acetylation of
the N-methylaminomethyl moiety and deprotection of the
tert-butyl ester with trifluoroacetic acid (TFA) yielded
the compound 2v in 36% yield. The 2-isopropylamino-
receptor.16 Furthermore, the rat plasma exposures at
1 h, 2 h, and 8 h after oral administration (3 or 10 mg/
kg) were examined to predict a compounds oral
bioavailability and duration of their plasma exposures.
The binding affinity of the 2-isopropylamino-7-(2-sub-
stituted - 4 - methoxyphenyl)cyclopenteno[1,2- b]pyridine
derivatives (1, 2a–x) toward the ETA and ETB receptors
and their selectivity for the ETA receptor over the ETB
receptor are shown in Tables 1 and 2. The 7-(2-hydroxy-
4-methoxyphenyl) derivative 1 was a potent ETA recep-
tor selective antagonist. Methylation (2a) of the phenol
moiety of 1 improved the binding affinity for the ETA
receptor, while the other alkylated derivatives (2b–f)
except for 2d resulted in decreasing the binding affinity
for the ETA receptor.
Table 1. In vitro potency of the cyclopenteno[1,2-b]pyridine derivatives
(1, 2a–h)
7-(2-substituted
alkyl-4-methoxyphenyl)cyclopenteno
[1,2-b]pyridines (2j–u,w,x) were prepared via Stille
coupling11 or Heck reaction13 of the optically active
triflate 10 with an appropriate reagent such as allyl-
tributyltin or allyl alcohol. Subsequent functionalization
of the C-2 side chain produced the derivatives (2j–u) in
moderate to good yields (Scheme 4).14
a
IC50 (nM)
Selectivity
ETB/ETA
Compd
R
ETA
ETB
1
H
Methyl
Ethyl
n-Propyl
i-Propyl
0.22
0.047
0.74
0.41
0.11
0.86
0.80
0.057
0.036
290
25
45
100
88
420
480
78
1300
530
61
240
800
490
600
1400
1700
2a
2b
2c
2d
2e
2f
2g
2h
3. Biological properties
Compounds synthesized above were primarily evaluated
in the binding assay (inhibitory activity against 125I-
labled ET-1 binding to both the human ETA and ETB
receptors).15 Selected compounds were tested in the
isolated tissues assay using rabbit iliacartery in the
presence of 3% human serum albumin to examine
their functional antagonist activity toward the ETA
i-Butyl
Benzyl
2-Hydroxy-1-methylethylb
2-Hydroxy-1-methylethylb
61
a Values are the mean of the two or more independent assay.
b Each of the two diastereomers on the side chain (R).

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H. Takahashi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1503–1507
Table 2. In vitro potency of cyclopenteno[1,2-b]pyridine derivatives
(2i–x)
Table 3. Biological properties of the cyclopenteno[1,2-b]pyridine
derivatives
Mouth lethality
AD50 (mpk, iv)
Rat plasma
exposure (nM)b
a
Compd
PKB
1 h
4 h
8 h
2g
2h
2i
2m
2p
2t
2u
2v
2w
7.46
8.00
7.76
8.33
NT
NT
0.046
0.12
0.034
0.042
0.042
0.039
NT
440
160
(130
(110
460
810
(220
(2
20
47
94
22
48
130
81
3
69
62
19)c
11)c
110
120
52)c
NT
8.33
8.97
NT
0.4)c
10
a
IC50 (nM) Selectivity
0.017
65
7
Compd
R
ETA ETB ETB/ETA
a Assays were performed in the presence of 3% human serum albumin.
Values are the mean of three or more independent assays.
b Compounds (10 mg/kg) were orally administered to rats (n=2–3),
otherwise noted.
2i
2j
2k
2l
Hydroxymethyl
2-Hydroxyethyl
3-Hydroxypropyl
0.062 62
0.031 19
0.022 20
0.059 51
0.041 54
0.011 11
0.045 15.7
0.014 14
0.065 23
0.011 6.0
0.048 5.6
0.011 25
0.025 48
1000
610
910
860
1300
910
350
1000
350
550
120
2300
1900
1600
1800
680
c Compounds (3 mg/kg) were orally administered to rats (n=2–3).
3-Hydroxy-2-methylpropylb
3-Hydroxy-2-methylpropylb
3-Hydroxy-2-ethylpropylc
3-Hydroxy-2-ethylpropylc
2-Hydroxy-2-methylpropyl
3-Hydroxy-3-methylbutyl
2,3-Dihydroxypropyld
2,3-Dihydroxylpropyld
3-Methoxy-2-methylpropyle
3-Methoxy-2-methylpropyle
2m
2n
2o
2p
2q
2r
2s
2t
2u
2v
2w
2x
functional antagonist activity in humans. The 3-
hydroxy-2-methylpropyl derivative 2m showed sub
nano-molar order of the intrinsicantagonist atcivity
(PKB: 10.0), while 2m showed decreased antagonist
activity (PKB: 8.33) in the presence of 3% HSA, sug-
gesting that 2m showed the considerable protein-bind-
ing shift. However, it was clear that all the tested
compounds retained high antagonist activity even in the
presence of 3% HSA (Table 3). In addition, these deri-
vatives showed excellent in vivo efficacy (AD50: 0.017–
0.12 mg/kg after intravenous administration) in the
mouse lethality model. These results suggested that the
high functional antagonist activity of these compounds in
the tissue assay well reflected their in vivo efficacy in mice.
N-Acetyl-N-methylaminomethyl 0.027 43
2-(N,N-Dimethylcarbamoyl)propylf 0.024 43
2-(N,N-Dimethylcarbamoyl)propylf 0.014 9.5
a Values are the mean of the two or more independent assay.
bÀf Each of the two diastereomers on the side chain (R).
The previous SARs on the prototype 7-[2-substituted-4-
methoxyphenyl]cyclopenteno[1,2-b]pyridine derivatives7
suggested that incorporation of a hydroxyalkyloxy-sub-
stituent at the C-2 side chain was tolerated in terms of
the ETA binding affinity and the selectivity for the ETA
over ETB receptor. In fact, incorporation of a hydroxyl
group into the isopropyl moiety of 2d improved the
potency (2g: IC50: 0.057 nM, 2h: IC50: 0.036 nM) for the
ETA receptor and the selectivity for the ETA receptor
over the ETB receptor (2g: ETB/ETA=1400-fold, 2h:
ETB/ETA=1700-fold). These results prompted us to
further investigate the SARs of the hydroxylated alkyl
derivatives (2i–u) on the ETA binding affinity and the
selectivity for the ETA receptor over the ETB receptor.
These derivatives showed excellent binding affinity
(IC50: 0.011ꢁ0.065 nM) for the ETA receptor. Com-
parison of the ETA selectivity of the two diastereomers
on the side chain at the 2-position of the bottom phenyl
ring [2-methyl- (2l and m), 2-ethyl- (2n and o) and 2-
hydroxyl- (2r and s) 3-hydroxypropyl derivatives] sug-
gested that the stereochemical structures of the side
chain affected the selectivity for the ETA over the ETB
receptor.
Improvement of the oral bioavailability of this class is a
key to success for the development of ETA receptor
selective antagonists, because the prototype dicarboxylic
acid derivatives7 showed poor oral absorption in the rat
in situ intestinal absorption study. Therefore, screening
of compounds by assessing their plasma levels at 1 h, 4
h and 8 h after oral administration (3 or 10 mg/kg) to
rats was performed to identify ETA receptor selective
antagonists with high orally bioavailability. Among the
hydroxyalkoxy and hydroxyalkyl derivatives, the 2-
hydroxy-1-methylethoxy (2g) and hydroxyalkyl (2i,m,
and 2p) derivatives showed moderate plasma exposures
at 1 h after oral administration, if the plasma exposures
of the compounds (2i and m) at 3 mg/kg were extra-
polated to 10 mg/kg. However, these derivatives had
different characteristics in terms of the duration of the
plasma exposures. The hydroxymethyl derivative 2i had
relatively high plasma exposure at 4 h, while the 3-
hydroxy-2-methylpropyl derivative 2m showed approxi-
mately 4-fold lower plasma exposure at 4 h than 2i.
These results suggested that 2i would have higher bioa-
vailability in rats than 2m. Indeed, the bioavailability of
these derivatives (2i and m) in rats (3 mpk, po and 1
mpk, iv) were 57% and 7.6%, respectively.
The biological properties of the derivatives exhibiting
greater than 1000-fold selectivity for the ETA over ETB
receptor were further characterized (Table 3). The iso-
lated tissue assays of these derivatives using the rabbit
iliacartery were performed in the presenec of 3%
human serum albumin (HSA) to predict a compounds
The 3-methoxy-2-methylpropyl derivatives (2t and u)
showed higher plasma exposure levels at 1 h, 4 h, and 8 h

H. Takahashi et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1503–1507
1507
after oral administration when compared with those of
the 3-hydroxy-2-methylpropyl derivative 2m. Particu-
larly, the bioavailability of 2u in rats (3 mpk, po and 1
mpk, iv) was 70%. In contrast, the 2-(dimethylcarba-
moyl)propyl derivatives (2v and w) showed extremely
lower plasma exposure levels at 1 h than the above
hydroxyalkyl and methoxypropyl derivatives, probably
due to their more hydrophilicnatures.
Nguyen, B.; Marsh, K. C.; Opgenorth, T. J. J. Med.
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(b) Elliot, J. D.; Lago, M. A.; Cousins, R. D.; Gao, A.;
Leber, J. D.; Erhard, K. F.; Nambi, P.; Elshourbagy,
N. A.; Kumar, C.; Lee, J. A.; Bean, J. W.; Debrosse,
C. W.; Eggleston, D. S.; Brooks, D. P.; Feuerstein, G.;
Ruffolo, R. R.; Weinstock, J.; Gleason, J. G.; Peishoff,
C. E.; Ohlstein, E. J. Med. Chem. 1994, 37, 1553. (c)
Walsh, T. F.; Fitch, K. J.; Chakravarty, P. K.; Williams,
D. L.; Murphy, K. A.; Nolan, N. A.; O’Brien, J. A.; Lis,
E. V.; Pettibone, D. J.; Kivlighn, S. D.; Gabel, R. A.;
Zingaro, G. J.; Krause, S. M.; Siegl, P. K. S.; Clin-
eschmidt, B. V.; Greenlee, W. J. Abstracts of American
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August 21–25, 1994, American Chemical Society:
Washington, DC, 1994; Medicinal Chem. No. 145. (d)
Amberg, W.; Hergenroder, S.; Hillen, H.; Jansen, R;
Kettschau, G.; Kling, A.; Klinge, D.; Raschack, M.; Rie-
chers, H.; Unger, L. J. Med. Chem. 1999, 42, 3206.
7. (a) Niiyama, K.; Mase, T.; Takahashi, H.; Naya, A.;
Katsuki, K.; Nagase, T.; Ito, S.; Hayama, T.; Hisaka, A.;
Ozaki, S.; Ihara, M.; Yano, M.; Fukuroda, T.; Noguchi,
K.; Nishikibe, M.; Ishikawa, K. Bioorg. Med. Chem. 2002,
10, 2461. (b) Niiyama, K.; Takahashi, H.; Nagase, T.;
Kojima, H.; Amano, Y.; Katsuki, K.; Yamakawa, T.;
Ozaki, S.; Ihara, M.; Yano, M.; Fukuroda, T.; Nishikibe,
M.; Ishikawa, K. Bioorg. Med. Chem. Lett. 2002, 12, 3041.
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K. Bioorg. Med. Chem. 2002, 10, 3437.
In conclusion, we have extensively derivatized the sub-
stituent at the 2-position of the bottom 4-methoxy-
phenyl ring on the cyclopenteno[1,2-b]pyridine core to
identify potent, orally bioavailable ETA receptor selec-
tive antagonists in this class. As a result, the 2-hydroxy-
1-methylethoxy (2g and h), hydroxyalkyl (2i, m, and p),
N-acetyl-N-methylaminomethyl (2v), and 2-(dimethyl-
carbamoyl)propyl (2w) derivatives that showed greater
than 1000-fold selectivity for the ETA receptor over the
ETB receptor with excellent binding affinity (IC50<0.10
nM) have been identified. Furthermore, the rat plasma
exposure screening of the compounds at 1 h, 4 h, and 8
h after oral administration led to identification of the
hydroxymethyl (2i) and 3-methoxy-2-methylpropyl (2u)
derivatives as having good oral bioavailability (2i: 57%,
2u: 70%) in rats. The 3-methoxy-2-methylpropyl deri-
vative 2u showed the interesting in vivo efficacy in
rats.17 The in vivo efficacy of the hydroxymethyl deri-
vative 2i will be reported in the near future.
References and notes
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silica gel column chromatography.
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