N-(1-Benzylpyrrolidin-3-yl)arylbenzamides as potent and selective human dopamine D4 antagonists

Article abstract of DOI:10.1016/j.bmcl.2004.07.045

A series of N-(1-benzylpyrrolidin-3-yl)arylbenzamides 8 has been prepared, and their structure-activity relationships studied. Potent ligands selective for human D₄ (hD₄) over hD₂ and α₁ have been identified. One example was determined to be an antagonist in a cAMP assay, with an IC₅₀ of 1500 nM. A series of N-(1-benzylpyrrolidin-3-yl)arylbenzamides 8 has been prepared, and their structure-activity relationships studied. Potent ligands selective for human D₄ (hD₄) over hD₂ and α₁ have been identified. One example was determined to be an antagonist in a cAMP assay, with an IC₅₀ of 1500 nM.

Full text of DOI:10.1016/j.bmcl.2004.07.045

Bioorganic & Medicinal Chemistry Letters 14 (2004) 4847–4850
N-(1-Benzylpyrrolidin-3-yl)arylbenzamides as potent and
selective human dopamine D4 antagonists
Ian Egle,* Nancy Barriault, Michel Bordeleau, Jillian Drage, Laurence Dube,
Jack Peragine, Lucy Mazzocco, Jalaj Arora, Keith Jarvie and Ashok Tehim
NPS Pharmaceuticals Inc., 6850 Goreway Dr., Mississauga, Ontario, Canada L4V 1V7
Received 27 April 2004; revised 21 July 2004; accepted 22 July 2004
Available online 20 August 2004
Abstract—A series of N-(1-benzylpyrrolidin-3-yl)arylbenzamides 8 has been prepared, and their structure–activity relationships
studied. Potent ligands selective for human D4 (hD4) over hD2 and a1 have been identified. One example was determined to be
an antagonist in a cAMP assay, with an IC50 of 1500nM.
Ó 2004 Elsevier Ltd. All rights reserved.
Dopamine D4 selective antagonists have received
renewed attention recently as potential therapeutics for
the treatment of sexual dysfunction, attention-deficit
hyperactivity disorder (ADHD), and other related disor-
ders. To be complete however, a history of these agents
must begin with a recount of their failed development as
antipsychotics.
Clozapine 2 was the first widely prescribed medication
that exhibited efficacy in the alleviation of both positive
and negative symptoms of schizophrenia.5 Its use has
been limited by the risk of development of potentially
fatal agranulocytosis.6 It also often fails to improve cog-
nitive function.7 Clozapine possesses a complicated
pharmacological profile, with a D4 affinity that is an
order of magnitude greater than its D2 affinity.8 This,
along with the observation that D4 expression levels
are elevated in the brains of schizophrenics, led to the
initiation of several research programs aimed at devel-
oping D4 selective antagonists, with the hope that such
compounds would be efficacious against both positive
and negative symptoms, and also lack the serious side
effects of existing drugs.
Schizophrenia is a devastating illness that affects up to
1% of the worldwide population.1 It is a particularly tra-
gic disease because the most severe symptoms typically
manifest in early adulthood, what would otherwise be
the prime of life.2 The symptoms of the disease are cat-
egorized into positive (e.g., hallucinations), negative
(e.g., anhedonia and poverty of speech), and cognitive
deficits. For years the positive symptoms of schizophre-
nia have been adequately controlled by neuroleptic med-
ications. These drugs, such as haloperidol 1, are D2
antagonists. Unfortunately, they are not as effective at
controlling the negative or cognitive symptoms of the
disease,3 and long-term neuroleptic treatment can pre-
cipitate serious side effects such as tardive dyskinesia.
These side effects often remain after neuroleptic treat-
ment is terminated.4
H
OH
N
Cl
O
N
Cl
N
N
F
N
1
2
Several such D4 selective antagonists were developed
and studied in clinical trials for the treatment of schizo-
phrenia, including L-745,870 3,9 and PNU-101387G 4,10
however none of them were found to be effective for
this particular indication.11 Recent evidence has been
mounting for the application of D4 selective antagonists
for the treatment of sexual dysfunction, ADHD,
Keywords: Dopamine; D4 antagonists.
*
Corresponding author. Tel.: +1 905 677 0831; fax: +1 905 677
9595; e-mail: iegle@npsp.com
Present address: Memory Pharmaceuticals Corp., 100 Philips Park-
way, Montvale, NJ 07645, USA.
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.07.045

4848
I. Egle et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4847–4850
ParkinsonÕs disease, or mood disorders.12 It is this re-
newed interest that has encouraged us to report our
identification of the highly selective hD4 antagonists
herein.13
N
O
O
N
H
O
N
5
Cl
Cl
H
N
N
The hD2 and hD4 receptor binding profiles of com-
pounds 8a–s were evaluated by their ability to dis-
N
N
H
3
place H-spiperone, using clozapine as a reference. For
3
the purposes of this assay, human embryonic kidney
298 cells were stably transfected with hD4 (D4.2 subtype)
receptor, and GH4C1 (rat pituitary) cells were stably
transfected with hD2 (short isoform) receptor. Rat fron-
tal cortex tissue was used for the a1 assay, using 7-meth-
oxy-[3H]-prazosin as the radioligand and clozapine as
the reference. Ki values for each compound were calcu-
lated by the Cheng and Prusoff transformation, and
are reported here as the mean of at least two determina-
tions, plus or minus the standard error of the mean.13
N
N
O
SO2NH2
4
As a starting point we used YM-43611 5, a dopamine
antagonist discovered by Yamanouchi Pharmaceuti-
cals.14 YM-43611 is a broad-spectrum dopamine ligand,
with affinities for the D2, D3, and D4 receptors of 220,
21, and 2.1nM, respectively. The compounds for this
study were prepared from commercially available 1-ben-
zyl-3-aminopyrrolidine 6 in either its racemic, or enan-
tiomerically pure forms. Compounds 8a to 8j were
synthesized by a direct acylation reaction with the
appropriate acid chloride. Compounds 8k to 8s were
prepared in the two-step procedure outlined in Scheme
1. Pyrrolidine 6 was first acylated with either 3- or 4-iodo-
benzoyl chloride to provide the aryl iodide 7a or 7b,
respectively,15 which was subjected to typical Suzuki
reaction conditions with the appropriate boronic acids
in a parallel synthesis to yield final compounds 8k–s.16
These were determined to be of sufficient purity for
pharmacological assessment by 1H NMR following col-
umn chromatography. The chiral purity of the final
compounds was not assessed, as it was believed to be un-
likely that erosion of the enantiomeric purity would
have occurred under the reaction conditions employed.
The binding data for compounds 8a–s at the human D2,
D4, and a1 receptors is presented in Table 1. In general
all of the compounds reported here exhibited good selec-
tivity for D4 versus D2 or a1. There was a general pref-
erence for the S enantiomer versus the R, not only were
the S enantiomers more potent at the D4 receptor (com-
pare for example 8m and 8n), but in addition these
enantiomers were also significantly less potent at the
a1 receptor, leading to a marked improvement in the
selectivity ratio between these two receptors. The D2
affinity did not show a clear preference for either enantio-
mer. Methylation of the amide nitrogen of 8p substan-
tially decreased the affinity for D4 (40% inhibition @
100nM), as well as D2 and a1 (7.4% and 0.29%, respec-
tively, @ 100nM). Replacement of the amide with a sul-
fonamide also dramatically reduced affinity for all three
receptors. For example, the sulfonamide analogue of 8n
exhibited 13% inhibition @ 100nM for the D4 receptor,
and was inactive at D2 and a1 @ 100nM.
I
(a)
N
N
N
NH2
*
H
*
O
6
7a-b
(b)
(c)
Ar
Ar
N
N
N
H
N
*
*
H
O
O
8a-j
8k-s
Scheme 1. Reagents and conditions: (a) 3- or 4-iodobenzoyl chloride, Et3N, CH2Cl2; (b) aroyl chloride, Et3N, CH2Cl2; (c) ArB(OH)2, Pd(PPh3)4,
Na2CO3, DME, D.

I. Egle et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4847–4850
Table 1. Binding profile of series 8 at the hD4, hD2, and a1 receptors
4849
Compound
Biaryl isomer
Ar
D4 Ki (nM)a
D2 Ki (nM)a
a1 Ki (nM)a
*
8a
rac-
para-
17
24
5
2
8000 6000
N.D.b
N.D.
CF3
NH2
8b
rac-
para-
5000 2000
8c
8d
rac-
rac-
para-
para-
17
3
6
1
4000 3000
600 200
N.D.
N.D.
S
8e
8f
rac-
rac-
rac-
rac-
meta-
para-
para-
para-
4
8
1
5
7
2
150 90
120 20
N.D.
N.D.
N.D.
N.D.
F
F
8g
8h
17
5
4000 1000
2600 300
Cl
O
8i
rac-
para-
36
2
3100 800
N.D.
H
S
H
8j
rac-
rac-
para-
para-
70 30
3700 300
840 30
N.D.
N.D.
O
S
8k
3
1
8l
rac-
R-
para-
para-
2.0 0.7
24
1200 400
1500
N.D.
330
S
S
8m
8n
8o
S-
para-
para-
3
980
1200
S
S
S
S
R-
18
8
900 300
170 50
8p
8q
S-
para-
meta-
2
1000
610
R-
3.4 0.6
94
4
170 30
8r
8s
S-
S-
meta-
meta-
2
1
70 20
60 20
140 30
160 50
S
1.5 0.3
a Ki values are reported as the mean of at least two independent determinations SEM. Where no SEM is reported, only a single determination was
made.
b N.D. = not determined.

4850
I. Egle et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4847–4850
7. Lee, M. A.; Thompson, P. A.; Meltzer, H. Y. J. Clin.
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In order to determine whether these compounds pos-
sessed antagonist functional activity, the ability of 8d
to reverse the dopamine inhibition of forskolin-stimu-
lated adenyl cyclase activity in Chinese hamster ovary
cells stably expressing hD4 receptor was measured.
Compound 8d was found to have an IC50 of 1500nM
in this assay, and thus is an antagonist of the hD4 recep-
tor. The reasons for the discrepancy between this result
and the binding Ki of 3nM are not clear from the pre-
sent data. Owing to the structural similarity of the other
compounds in this study, it reasonable to assume that
they are likely also D4 antagonists. Similarly, adminis-
tration of 8d plus forskolin to the same cell line failed
to decrease the cAMP concentration in the cells below
the level resulting from administration of forskolin
alone. Thus, it can be expected that these compounds
are unlikely to possess significant D4 agonist activity.13
8. Tamminga, C. A. Can. J. Psychiat. 1997, 42, 265–273.
9. Kulagowski, J. J.; Broughton, H. B.; Curtis, N. R.;
Mawer, I. M.; Ridgill, M. P.; Baker, R.; Emms, F.;
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Eaton, M. J.; Lookingland, K.; Lutzke, B. S.; Mccall, R.
B.; Piercey, M. F.; Schreur, P. J.; Sethy, V. H.; Smith, M.
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2764–2772.
15. To a solution of 6 (100mg, 0.567mmol) in CH2Cl2 (2mL)
at 0°C was added Et3N (0.79mL, 574mg, 5.67mmol) and
4-iodobenzoyl chloride (151mg, 0.567mmol). After 1h the
reaction mixture was poured into saturated NaHCO3 and
extracted with CH2Cl2. The organic phase was dried
(Na2SO4), filtered, and concentrated to provide 7b
(196mg, 85%).
This body of work has successfully identified a novel
class of highly potent D4 antagonists that are selective
over D2 and a1. Selective D4 antagonists might be
of value in the treatment of disorders including sexual
dysfunction, ADHD, ParkinsonÕs disease, and mood
disorders.
References and notes
16. As a representative procedure, to a solution of 7b (10.0g,
24.6mmol) in DME (400mL) was added thiophene-2-
boronic acid (6.30g, 49.24mmol), Pd(PPh3)4 (1.42g,
1.23mmol), and 2M Na2CO3 (100mL). The mixture was
refluxed for 8h, cooled, poured into water, and extracted
with EtOAc. The organic phase was washed with brine,
dried (Na2SO4) and charcoaled, filtered, and concentrated.
Column chromatography (1% NH4OH/5% MeOH/94%
CH2Cl2) provided 8k (5.90g, 66%) as an off-white solid.
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1
Compound 8k: H NMR (300MHz, CDCl3) d 1.71–1.87
(m, 1H), 2.32–2.48 (m, 2H), 2.67 (dd, 1H), 2.79 (dd, 1H),
2.92–3.03 (m, 1H), 3.69 (s, 2H), 4.64–4.75 (m, 1H), 6.66
(br d, 1H), 7.12 (dd, 1H), 7.25–7.37 (m, 6H), 7.39 (dd, 1H),
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