2-Phenyl-4(5)-[[4-(pyrimidin-2-yl)piperazin-1-yl]methyl]imidazole. A highly selective antagonist at cloned human D4 receptors

Full text of DOI:10.1021/jm960637m

© Copyright 1997 by the American Chemical Society
Volume 40, Number 1
J anuary 3, 1997
Communications to the Editor
2-P h en yl-4(5)-[[4-(p yr im id in -2-
N
yl)p ip er a zin -1-yl]m eth yl]im id a zole. A
High ly Selective An ta gon ist a t Clon ed
Hu m a n D4 Recep tor s
N
R1
N
N
H
N
N
R3
Cl
R2
N
H
Andrew Thurkauf,* J un Yuan, Xi Chen,
Xiao Shu He, J an W. F. Wasley, Alan Hutchison,
Kristine H. Woodruff, Robin Meade,
Diane C. Hoffman, Hilary Donovan, and
Deborah K. J ones-Hertzog
1
2
R1
N
Neurogen Corporation, 35 Northeast Industrial Road,
Branford, Connecticut 06405
N
H
N
Received September 9, 1996
N
The neuroleptic agent clozapine (1) has been referred
to as an atypical antipsychotic because it does not
induce the extrapyramidal motor side effects charac-
teristic of all other antischizophrenia medications.1,2 The
discovery that clozapine displays a higher affinity for
dopamine D4 receptors than D2 receptors3 coupled with
the controversial4 finding that D4 receptor density is
elevated in schizophrenic relative to nonschizophrenic
postmortem brain tissue5,6 has led to the postulate that
dysfunction of the D4 system is, at least in part, involved
in the etiology of schizophrenia. A number of ligands
selective for the D4 receptor subtype have recently been
reported.7
X
W
Y
Z
3
mercially available reagents 2-phenyl-4-methylimida-
zole (7) and 1-(2-pyrimidinyl)piperazine (6). Methods
for the preparation of 5 have been previously described.8
The binding affinities of compounds 3a -h for cloned
human D2, D3, and D4 receptors are shown in Table 1.
Binding affinities (Ki) of 3a -h at cloned D1 and D5
receptors were greater than 5000 nM.
Previously we reported on a series of 2-phenyl-4-
(aminomethyl)imidazoles (2) which displayed affinity at
dopamine D2 receptors.8 Expansion of this work lead
us to investigate modifications of the aminomethyl
group within this series, eventually leading to the
preparation of various aryl- and heteroarylpiperazine
derivatives of general structure 3. Receptor binding in
cloned human receptors indicated such modification
within this structural class produced a series of com-
pounds with greatly improved D4/D2 binding ratios.
The synthetic methods used in the preparation of the
compounds 3a -3g are shown graphically in Scheme 1.
The compounds (except 3h ) were prepared by the
alkylation of the appropriate 1-aryl- or 1-heteroarylpip-
erazine (4) with 2-phenyl-4-(chloromethyl)imidazole (5)
in the presence of triethylamine. Compound 3h was
prepared via a Mannich reaction between the com-
The unsubstituted phenyl derivative 3a displayed
appreciable affinity at both D2 and D4 receptors and a
D2/D4 ratio of approximately 50. Use of pyridyl, pyra-
zinyl, or pyrimidinyl heterocycles in place of phenyl
resulted in attenuation of D2 receptor binding in all
cases except 3c. Dopamine D4 affinity was also affected
by changes in the arylpiperazine portion of the molecule.
Of the three possible pyridyl derivatives, only the
2-pyridyl (3b) retained significant affinity at the D4
receptor. Among the diazaheterocycles, the 2-pyrazinyl
(3e) and 4-pyrimidinyl (3f) compounds displayed dimin-
ished D4 binding (similar to their direct monoaza
analogs 3c and 3d ), while the D4 binding of the
2-pyrimidinyl compound 3g was largely unaffected by
the additional nitrogen. Its D2/D4 binding ratio of
approximately 675 was the best among the compounds
tested. Examination of the binding results indicates
S0022-2623(96)00637-1 CCC: $14.00 © 1997 American Chemical Society

2
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1
Communications to the Editor
Sch em e 1. Synthesis of
2-Phenyl-4-(1-[piperazin-1-yl])methylimidazoles.
The favorable dopamine receptor binding results
obtained for 3g prompted a closer examination of the
compound. Further receptor binding studies revealed
no significant affinity (<1000 nM) for a wide variety of
CNS and non-CNS receptor systems with the exception
of 5-HT1a (Ki ) 181 nM).
H
N
N
N
N
N
H
N
In a series of biochemical experiments, the antago-
nistic properties of 3g on the D4 receptor were demon-
strated. It has been shown that D4 receptors are
coupled to G-proteins.9 The D4 receptor is also nega-
tively linked to adenylate cyclase such that agonists at
D4 receptors inhibit forskolin-stimulated cAMP produc-
tion. Neither 3g nor the dopamine agonist quinpirole
had any effect on the basal (non forskolin stimulated)
amount of cAMP formed in the D4 receptor expression
system. The addition of forskolin, which directly acti-
vates adenylate cyclase, caused a significant increase
in cAMP levels. This increase was inhibited by the
agonist quinpirole in a dose dependent fashion. Com-
pound 3g did not inhibit forskolin-stimulated cAMP
production, but produced a 50% attenuation of the
quinpirole-induced inhibition of cAMP production. Thus,
3g exerts functional antagonism within the D4 receptor
system.
W
X
Y
base
N
H
+
Cl
N
Z
5
4
X
W
Y
Z
3a–g
H
N
CH3
N
CH3
N
N
N
H
N
HCHO
N
H
N
N
+
N
7
6
N
N
3h
Behavioral testing for antipsychotic efficacy was then
carried out on 3g. At relatively low doses (0.1, 0.5
and1.0 mg/kg sc), 3g significantly (p < 0.05) attenuated
the disruptive effects of apomorphine (20 mg/kg sc) on
prepulse inhibition. This effect is consistent with that
of other antipsychotic drugs in this model.10 In behav-
ioral assays of extrapyramidal side effect (EPS) li-
ability,11,12 3g failed to block either apomorphine or
amphetamine-induced stereotypy and did not induce
catalepsy over a wide dose range (0.1-10.0 mg/kg sc).
These tests suggest a low EPS liability for 3g in
humans. In behavioral assays of CNS depression and
sedation,13 3g displayed no consistent effects on spon-
taneous locomotor activity and did not affect the am-
plitude of the response in acoustic startle. All behav-
ioral testing was carried out using male Sprague-
Dawley rats.
that replacement of the phenyl group of 3a with a 2-aza
heterocycle such as 2-pyridyl or 2-pyrimidinyl is not only
tolerated but leads to a significant improvement in the
D2/D4 binding ratio. In contrast, replacement of the
phenyl of 3a by a 3- or 4-aza heterocycle reduces
dopamine receptor binding. This is true even in those
cases where a 2-aza moiety is also present in the same
structure (i.e. 3e, 3f).
Compound 3h was prepared as a conformationally
restricted analog of 3g. Molecular mechanics studies
confirmed that the barriers to free rotation about the
methylene group at the C-4 position on the imidazole
of 3h were higher than those of 3g. The fact that good
D4 binding and selectivity were retained by 3h suggests
that the binding conformation of this series to D4
receptors is as shown in structure 3 rather than the
alternative extended conformation.
Ta ble 1. Affinities of 2-Phenyl-4-(piperazin-1-ylmethyl)imidazoles at Cloned Human Dopamine Receptors
Ki (nM)a
compound
W
X
Y
Z
R1
D2
D3
D4
3a
3b
3c
3d
3e
3f
3g
3h
C
C
C
C
N
C
N
N
C
N
C
C
C
N
N
N
C
C
N
C
N
C
C
C
C
C
C
N
C
N
C
C
H
H
H
H
H
H
H
Me
254 ( 41
2190 ( 190
296 ( 42
193 ( 31
1530 ( 680
289 ( 31
5.2 ( 1.3
8.5 ( 1.5
73 ( 1
>3500
>8000
>7300
>4130
>4130
2250 ( 440
1440 ( 94
4.8 ( 1.2
254 ( 19
>6665
>8000
>8000
2980 ( 1390
nd
50 ( 9
1400 ( 120
3.8 ( 0.7
6.0 ( 0.9
7.3 ( 1.3
70 ( 11
haloperidol
clozapine
454 ( 39
a
Binding data are the means of at least three independent experiments using standard displacement assays with [3H]YM 09151 as
the competitive ligand and human dopamine receptor subtypes expressed in CHO cells.

Communications to the Editor
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1
3
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F.; Marwood, R.; Patel, S.; Patel, S.; Ragan, C. I.; Freedman, S.
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In conclusion, the relatively modest D4 selectivity of
2-phenyl-4-[(4-phenylpiperazin-1-yl)methyl]imidazole (3a)
could be greatly amplified by replacement of the phe-
nylpiperazine with either 2-pyridylpiperazine (3b) or
2-pyrimidinylpiperazine (3g). The interesting binding
and behavioral profile of 3g has led to its selection as a
clinical candidate for the treatment of schizophrenia.
Su p p or tin g In for m a tion Ava ila ble: Synthetic proce-
1
dures, melting points, and H NMR data for all products plus
a molecular modeling study (7 pages). Ordering information
is given on any current masthead page.
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