Two novel and potent 3-[(o-Methoxyphenyl)piperazinylethyl]-5-phenylthieno[2,3-d]pyrimidine-2, 4-diones selective for the α1D receptor

Article abstract of DOI:10.1016/S0960-894X(01)00159-7

The synthesis and in vitro characterization of A-119637 and A-123189, two novel, selective and potent α_1D antagonists, are described.

Full text of DOI:10.1016/S0960-894X(01)00159-7

Bioorganic & Medicinal Chemistry Letters 11 (2001) 1119–1121
Two Novel and Potent 3-[(o-Methoxyphenyl)piperazinylethyl]-5-
phenylthieno[2,3-d]pyrimidine-2,4-dionesSelective for the ꢀ1D
Receptor
William A. Carroll,* Kevin B. Sippy, Timothy A. Esbenshade, Steven A. Buckner,
Arthur A. Hancock and Michael D. Meyer
Abbott Laboratories, Neurological and Urological Diseases Research, 100 Abbott Park Road, Abbott Park, IL 60064-6101, USA
Received 14 December 2000; accepted 19 February 2001
Abstract—The synthesis and in vitro characterization of A-119637 and A-123189, two novel, selective and potent a1D antagonists,
are described. # 2001 Elsevier Science Ltd. All rights reserved.
To date, three distinct subtypes of the a1-receptor have
been identified by both molecular biological (a1a, a1b,
and a1d) and classical pharmacological (a1A, a1B, and
has been the absence of highly potent and selective
ligands devoid of ancillary pharmacology. For example,
BMY7378 possesses equal affinity at the rat 5-HT1A and
a1d receptors.9 Likewise, the a1d selective benzazepines
SK&F 104856 and SK&F 106686 possess significant
activity at the a2b receptor.10 More recently, SNAP8719,
an analogue of BMY7378, has been described as an a1d
ligand with similar or improved selectivity versus the
other a1 receptor subtypes and inactive at a range of
other receptors.11 In vitro functional characterization of
SNAP8719 has yet to be described in the literature.
Unlike many of the selective a1A antagonists, all of the
currently known a1d selective ligands have an affinity for
this receptor of around 1 nMor greater. Therefore, the
discovery of more potent subtype selective ligands
would undoubtedly facilitate study of the physiological
role played by the a1D receptor. We describe herein two
novel a1d selective antagonists with potencies of less
than 1 nMin both radioligand binding and in vitro
functional assays.
a
1D) means.1 Defining the physiological roles of the a1
subtypes in various organs has been the subject of
intensive research efforts. The preponderance of evi-
dence currently supports the hypothesis that the a1A
receptor is primarily responsible for mediating adrener-
gic prostatic tone.2 The therapeutic relevance of these
findings has been borne out in the clinical setting with
BPH patients where tamsulosin (a1a:a1b selectivity
ꢀ20Â)3 has been reported to possess improved prostate
selectivity relative to earlier non-subtype selective
agents.4 Equally well-defined roles for the a1B and a1D
subtypes have yet to be established. Several lines of evi-
5
6
dence point to the importance of the a1B and a1D
receptors in the maintenance of vascular tone. In the
human bladder detrusor, a1d mRNA has been shown to
be the dominant a1 subtype.7 In a related study, the a1D
selective antagonist BMY7378 reportedly inhibited
involuntary detrusor contractions in a rat model of
bladder outlet obstruction.8 Thus, it has been suggested
that a1D receptor blockade may ameliorate the irritative
symptoms of BPH that result from involuntary con-
tractions of the bladder smooth muscle.
A major factor that has limited the ability to conduct
definitive in vivo studies on the role of the a1D receptor
*Corresponding author. Fax: +1-847-935-5466; e-mail: william.a.
carroll@abbott.com
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00159-7

1120
W. A. Carroll et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1119–1121
The title compounds described in this report were pre-
pared in a straightforward fashion according to the
method of Russell et al.12,13 (Scheme 1). Briefly, the
2-amino-3-carboethoxythiophenes (1) were condensed
with an o-chloroalkylisocyanate in toluene at reflux,
followed by reaction of the intermediate o-chloroalkyl-
ureas with 2-methoxyphenylpiperazine and cyclization
to the thienopyrimidine-2,4-diones by treatment with
potassium tert-butoxide. Methylation of the N-1 posi-
tion was accomplished by reaction with NaH then MeI.
The starting substituted 2-amino-3-carboethoxy-
thiophenes were synthesized as described by Gewald.14
a1a receptor than for the human a1a and rat a1A recep-
tors. Relative to the a1d selective ligand BMY7378, both
A-119637 and A-123189 have approximately 3Â greater
binding affinity for the human a1d receptor, although
also correspondingly lower selectivity for a1d over a1a
and a1b. The unsubstituted compound 2d possesses only
4-fold selectivity for a1d over a1b and is nonselective for
a1d versus a1a. Extending the chain length to three car-
bons results in a 40-fold decrease in affinity for the a1d
receptor and a total loss of selectivity (compound 2f).
Moving the phenyl substituent to the 6 position (com-
pound 2e) reduces the selectivity to a level comparable
with the unsubstituted compound 2d. The 6-methyl-5-
phenyl substitution pattern (compound 2c) produces a1d
selectivity qualitatively similar to A-119637 and A-123189.
Moving the methyl group to the N-1 position (com-
pound 3) reduces affinity for the a1d receptor while
having little effect on the a1a and a1b subtypes. It
appears therefore, that the 5-phenyl substituent is
responsible for the a1d selectivity versus a1a and imparts
additional selectivity over a1b relative to the core structure.
Compounds were evaluated for their binding affinities
at the cloned human and rat a1d receptors versus the
human a1a and a1b receptors as well as the bovine a1a
and tissue derived rat a1A from the rat submaxillary
gland.3 Functional antagonism was demonstrated using
the rat vas deferens, spleen and aorta as tissue models of
the a1A, a1B, and a1D receptors respectively.3 Ancillary
binding affinities at the a2a, a2B, a2c, D1, D2, 5-HT1, and
5-HT2 receptors were determined for two compounds.
Both A-119637 and A-123189 exhibit potent antagon-
ism in the a1D functional model, the rat aorta (Table 2)
and show ꢁ100-fold selectivity over the rat vas deferens
and spleen. Both of these compounds display over 100-
fold greater potency in the rat aorta than BMY7378.
Relative to BMY7378, A-119637 and A-123189 are less
a1d selective in their binding affinities (see Table 1),
however the tissue selectivities for the rat aorta are
equivalent or superior. The reason for the discrepancy
between these two readouts of a1D selectivity is
presently unknown.
With the exception of compound 2f, all compounds
displayed high affinity for the a1d receptors (Table 1). A-
119637 (2a) and A-123189 (2b) displayed selectivities
between 10- to 20-fold for the a1d receptor over the
human a1a and rat a1A receptors. Slightly greater selec-
tivities were observed for a1d versus a1b, with A-119637
being 18-fold selective and A-123189 29-fold selective
at the human clones. Interestingly, A-119637 and
A-123189 possess 10-fold greater affinity for the bovine
Compounds A-119637 and A-123189 were also screened
at the a2a, a2B, a2c, D1, D2, 5-HT1, and 5-HT2 receptors
Table 2. In vitro functional activitya
Compound
Rat vas deferensb
pA2
Rat spleenc
pA2
Rat aortad
pA2
A-119637
A-123189
BMY7378
8.07 (1.03)
8.36 (1.01)
5.98 (0.80)
8.69 (1.00)
8.76 (0.81)
7.37 (0.92)
10.6 (0.94)
10.7 (0.77)
8.22 (1.18)
aSchild slopes shown in parentheses.
ba1A
ca1B
da1D
Scheme 1. (i) Cl(CH2)nCH2NCO, toluene, reflux; (ii) 2-methoxy-
phenylpiperazine, Hunig’s base, acetonitrile, reflux; (iii) KOtBu,
ethanol, reflux; (iv) NaH, DMF; MeI.
.
.
.
Table 1. a1 Subtype radioligand binding Ki (nM)a
Compound
R1
R2
n
a
1A (rat)
a
1a (human)
a
1a (bovine)
a1b (human)
a
1d (human)
a1d (rat)
2a (A-119637)
2b (A-123189)
2c
2d
2e
2f
3
H
H
Me
H
Ph
H
H
Ph
m-Tolyl
Ph
H
H
Ph
Ph
—
—
1
1
1
1
1
2
1
—
—
2.43
3.47
1.97
0.523
0.578
9.58
2.62
2.63
4.17
2.63
0.344
0.868
8.49
3.10
0.274
0.348
0.377
0.181
0.248
1.25
0.436
43
NA
4.66
9.09
3.70
1.22
1.86
15.8
4.47b
94.3
165c
0.252
0.312
0.466
0.308
NT
7.15
NT
0.778
1.3c
0.213
0.170
0.251
0.229
0.361
8.20
0.710
0.959
NA
BMY7378
SNAP8719
112
NA
130
14,900c
—
aKi values the average of 3–6 determinations.
bHamster clone.
cValue from ref 11. NT=not tested. NA=not available.

W. A. Carroll et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1119–1121
Table 3. Ancillary binding profiles of A-119637 and A-123189
1121
Referencesand Notes
Receptorab
A-119637
A-123189
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e
a2a
77.8
71.0
74.7
6090
82.5
66.6
82.0
12300
17.0c
f
a2B
e
a2c
D1
f
f
D2
5-HT1
5-HT2
50.0
5490d (0.98)
137
12,300d (1.4)
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f
f
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aKi (nM).
bAverage of 3–6 determinations.
cTwo determinations.
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dHill slope in parentheses.
eCloned human receptor.
fNative rat receptor.
(Table 3) and found to have considerably less affinity
for all these receptors relative to the a1d receptor. The
low affinities of A-119637 and A-123189 for the 5-HT1
receptor with Hill slopes near unity suggest weak affi-
nity for the 5-HT1A receptor. This distinguishes these
compounds from BMY7378, for which the affinity at
the 5-HT1A receptor could be a potential confounding
factor in evaluating the in vivo functional role of the
a1D receptor. Activity at the D2 receptor was the great-
est source of cross reactivity for A-119637 and A-
123189, although the affinities versus a1d are still 50- to
100-fold weaker.
6. (a) Ibarra, M.; Terron, J. A.; Lopez-Guerrero, J. J.;
Molina, R. V. Eur. J. Pharmacol. 1997, 322, 221. (b) Zhou, L.;
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In conclusion, A-119637 and A-123189 are two novel,
selective and potent a1D antagonists in both the a1 clo-
nal cell lines and in in vitro tissue strips. These agents
share with BMY7378 and SNAP8719 the common
structural features of a substituted phenylpiperazine
and a heterocycle attached via a two-carbon linker. The
5-phenyl substitution on the heterocyclic attachment
was shown to impart the a1D selectivity.15
11. Konkel, M. J.; Wetzel, J. M.; Cahir, M.; Craig, D.; Noble,
S. A.; Gluchowski, C. Abstracts of Papers, 216th National
Meeting of the American Chemical Society, Boston, MA, Aug
23–27, 1998; American Chemical Society: Washington, DC,
1998; PMSE 129.
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J. J.; Falotico, R.; Keiser, J. A.; Bright, D. A.; Tobia, A. J.
Med. Chem. 1988, 31, 1786.
13. All new compounds described herein were characterized
by 1H NMR and mass spectroscopy, and gave satisfactory
elemental analyses (C, H, N).
14. Gewald, K.; Schinke, E.; Bottcher, H. Chem. Ber. 1966,
99, 94.
Acknowledgements
The authors would like to thank Ivan Milicic for tech-
nical assistance and W.A.C. would like to thank Marty
Winn for helpful chemistry discussions.
15. This substitution was chosen based upon the results of
molecular modeling studies that will be the subject of a future
publication.