Identification of a Potent and Selective 5-HT6 Antagonist: One-Step Synthesis of (E)-3-(Benzenesulfonyl)-2-(methylsulfanyl)pyrido[1,2-a]pyrimidin-4-ylidenamine from 2-(Benzenesulfonyl)-3,3-bis(methylsulfanyl)acrylonitrile

Article abstract of DOI:10.1021/jm034142q

(E)-3-(Benzenesulfonyl)-2-(methylsulfanyl)pyrido-[1,2-a] pyrimidin-4-ylidenamine (7) was found to be a potent and selective 5-HT ₆ antagonist. A one-step synthesis of this compound is described.

Full text of DOI:10.1021/jm034142q

4834
J . Med. Chem. 2003, 46, 4834-4837
Ch a r t 1
Id en tifica tion of a P oten t a n d Selective
5-HT6 An ta gon ist: On e-Step Syn th esis of
(E)-3-(Ben zen esu lfon yl)-2-
(m eth ylsu lfa n yl)p yr id o[1,2-a ]p yr im id in -
4-ylid en a m in e fr om
2-(Ben zen esu lfon yl)-3,3-
bis(m eth ylsu lfa n yl)a cr ylon itr ile
Yong-J in Wu,*,† Huan He,† Shuanghua Hu,|
Yazhong Huang,| Paul M. Scola,|
Katharine Grant-Young,| Robert L. Bertekap,‡
Dedong Wu, Qi Gao, Yi Li,§ Cheryl Klakouski,X and
Ryan S. Westphal‡
Bristol-Myers Squibb Pharmaceutical Research Institute,
5 Research Parkway, Wallingford, Connecticut 06492
Received J uly 9, 2003
Abstr a ct: (E)-3-(Benzenesulfonyl)-2-(methylsulfanyl)pyrido-
[1,2-a]pyrimidin-4-ylidenamine (7) was found to be a potent
and selective 5-HT6 antagonist. A one-step synthesis of this
compound is described.
Morris water maze.10 However, not all studies with AOs
have yielded similar behavioral phenotypes. For ex-
ample, in two additional studies, central administration
of 5-HT6 receptor AOs did not reproduce the cholinergic
phenotype of yawning/stretching/chewing, but did pro-
duce anxiogenic behavior in social interaction and
elevated plus maze tests.4,11 In these studies, a partial
decrease (25%) in 5-HT6 receptor expression was ob-
served as determined by immunohistochemical staining.
As none of the AO studies documented a complete
inhibition of 5-HT6 receptor expression, differences
between studies could be explained by differences in the
levels of inhibition of 5-HT6 receptor expression. Thus,
while the AO studies suggest that the 5-HT6 receptor
plays a role in CNS function, further understanding of
the specific role of the receptor required development
of 5-HT6 receptor ligands.
In tr od u ction . The 5-HT6 receptor is a member of the
family of receptors that mediate the physiological effects
of the neurotransmitter serotonin (5-HT).1-3 This recep-
tor belongs to the G-protein-coupled receptor super-
family and is positively coupled to adenylate cyclase.1-3
Evaluation of the expression pattern of 5-HT6 receptor
mRNA and protein revealed that it is selectively ex-
pressed in the central nervous system, exhibiting wide-
spread distribution throughout the brain.1-6 In addition,
the 5-HT6 receptor possesses high affinity for atypical
antipsychotics (e.g., clozapine) and tricyclic antidepres-
sants (e.g., amitriptyline and clomipramine).1,7 Thus,
5-HT6 receptor pharmacology and tissue expression
suggest that this receptor may have therapeutic utility
in CNS diseases.
Recently, several selective 5-HT6 receptor antagonists
have been developed including Ro 04-6790 (1, Chart 1),12
Ro 63-0563 (2),12 SB-271046 (3),13 SB-357134 (4),14
4-(2-bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)phenyl-
amine (5),15 and N1-(benzenesulfonyl)tryptamine 6.16
Several of these agents have been used to investigate
5-HT6 receptor function in vivo. Consistent with the
previous studies using AOs, Ro 04-6790 produced a
stretching behavior that was selectively blocked by
muscarinic antagonists, suggesting that the 5-HT6
receptor is involved in regulation of cholinergic signal-
ing.17 A role for the 5-HT6 receptor in processes of
learning and memory was also supported as SB-271046
and SB-357134 were efficacious in a spatial memory
task in rats18 and Ro 04-6790 improved learning con-
solidation in an autoshaping task.19 In addition, sys-
temic administration of SB-271046 selectively enhanced
the levels of excitatory amino acids within the frontal
cortex.20,21 While several studies suggest that 5-HT6
receptor antagonists may have utility as cognition
enhancers, not all studies have replicated these re-
sults.22 Therefore, the development of additional potent
and selective 5-HT6 receptor antagonists will provide
additional tools for delineating the role of the 5-HT6
Initial studies of 5-HT6 receptor function in vivo
utilized antisense oligonucleotides (AOs) to disrupt
5-HT6 receptor expression and evaluate the effects on
animal behavior. For example, rats administered 5-HT6
receptor AOs, but not control oligonucleotides, elicited
a yawning, stretching, and chewing behavioral syn-
drome that was blocked by the muscarinic antagonist
atropine.8,9 In this study a 30% decrease in [3H]lysergic
acid diethylamide (LSD) binding was observed, sug-
gesting that the antisense treatment decreased expres-
sion of 5-HT6 receptors. These results indicate that the
5-HT6 receptor functions as a negative regulator of
cholinergic signaling. A role for the 5-HT6 receptor in
processes of memory formation is supported by studies
demonstrating that administration of 5-HT6 receptor
AOs enhanced retention, but not acquisition, in the
* Corresponding author. Tel.: +1-203-677-7485; fax: +1-203-677-
7702; e-mail: yong-jin.wu@bms.com.
† Department of Neuroscience Chemistry.
| Department of Early Discovery Chemistry.
‡ Department of Neuroscience Biology.
Department of Analytical Sciences.
§ Department of Computer-Aided Drug Design.
X Department of Lead Profiling.
10.1021/jm034142q CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/11/2003

Letters
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 23 4835
Sch em e 1
Sch em e 2
F igu r e 1. Thermal ellipsoid plot (35% ellipsoids) of 7.
Crystallographic atom numbering.
receptor in vivo. In this report, we describe the discovery
of (E)-3-(benzenesulfonyl)-2-(methylsulfanyl)pyrido[1,2-
a]pyrimidin-4-ylidenamine (7, Chart 1) as a potent and
selective 5-HT6 antagonist and a one-step synthesis of
this compound.
Sch em e 3
Lea d Id en tifica tion a n d Ch em istr y. A four-point
pharmacophore model23 based on the known 5-HT6
receptor antagonists, Ro 04-6790 (1), Ro 63-0563 (2), and
SB-271046 (3), was used in a virtual screen to select a
set of compounds from the Bristol-Myers Squibb (BMS)
compound collection for evaluation in 5-HT6 radioligand
binding assays. In these assays, HEK293 membranes
containing recombinant human 5-HT6 receptors were
evaluated for displacement of [3H]lysergic acid diethyl-
amide (LSD) binding using known and novel 5-HT6
receptor ligands. Further analysis of compounds from
12 was treated with 9 in refluxing methanol, the
uncyclized product 13 was obtained exclusively as a
single isomer in 74% yield. X-ray diffraction analysis
of crystalline 13 showed the E configuration.26 Our
efforts to convert 13 into 14 under various conditions
(e.g., K2CO3 in DMF, Hu¨nig base in ethanol) met
without success.
this screen identified compound 7 as a potent (IC50
4
nM) inhibitor of [3H] LSD binding. In the same assay,
Ro 04-6790 showed an IC50 of 26.3 nM.
With compound 7 identified as a potent 5-HT6 an-
tagonist, we required a sizable amount of this compound
for further biological evaluations. As this compound was
acquired from another company more than three de-
cades ago, the synthesis protocol was unavailable within
BMS. To our knowledge, this compound is unknown in
the literature. Thus, a synthetic methodology was
developed. Gommper et al. had previously reported that
treatment of 2-(bis(methylsulfanyl)methylene)malono-
nitrile (8) with pyridin-2-ylamine (9) in ethanol under
reflux resulted in the tandem Michael addition-methyl-
sufanyl elimination-nucleophilic addition reactions
to provide 4-imino-2-methylsulfanyl-4H-pyrido[1,2-a]-
pyrimidine-3-carbonitrile (10) in 50% yield (Scheme 1).24
The amidine configuration was not disclosed. Thus, we
sought to determine if 7 could be prepared from 2-(ben-
zenesulfonyl)-3,3-bis(methylsulfanyl)acrylonitrile (11)25
in an analogous fashion. Indeed, when a solution of 9
and 11 in ethanol was heated under reflux, we obtained
the desired product 7 as a single isomer in 24% yield
(not optimized) after recrystallization from ethanol
(Scheme 2). The solid-state conformation of 7 was
determined by X-ray single-crystal analysis.26 As shown
in Figure 1, the hydrogen of the amidine group points
toward one of the sulfonyl oxygen atoms to form an
intramolecular hydrogen bond in a six-membered ring.
We also attempted to prepare the desmethylsulfanyl
analogue of 7 (i.e., 14, Scheme 3) from 2-(benzene-
sulfonyl)-3-methoxyacrylonitrile (12).27 However, when
Resu lts a n d Discu ssion . Compound 7 was evalu-
ated in 5-HT6 receptor functional assays using the
human receptor expressed in HeLa and HEK293 cells.
In these assays, we evaluated 5-HT6 receptor-mediated
activation of adenylate cyclase (data not shown) and
activation of Ca2+ mobilization via coexpression of the
G-protein subunit GR15 (Figure 2). Compound 7 an-
tagonized 5-HT stimulation of the 5-HT6 receptor in a
dose-dependent manner (Figure 2). To evaluate further
the antagonist properties of 7 at the 5-HT6 receptor,
5-HT dose-response curves were obtained in the pres-
ence of increasing concentrations of 7 and a Schild
analysis was performed (Figure 3). These studies dem-
onstrated the interaction of 7 with the 5-HT6 receptor
was consistent with properties of a competitive antago-
nist (slope -0.95; KD 4.7 nΜ). This compound also
exhibited no evidence of intrinsic activity at the receptor
as demonstrated by lack of effect by compound alone
(data not shown). Thus, the functional data demon-
strated that 7 is a 5-HT6 receptor antagonist.
Compound 7 was tested in a commercial screening
package (Cerep) and did not exhibit significant (i.e.
<20% inhibition at 10 µM concentration) interactions
at over 70 other receptors including all seven 5-HT
receptors assayed (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C
5-HT3, 5-HT5A, 5-HT7).
,
The cytochrome P450 inhibitory potential of 7 was
determined using recombinant human CYP1A2, CYP2C9,

4836 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 23
Letters
Ch a r t 2
F igu r e 2. Effect of 7 on 5-HT-stimulated calcium mobilization
in HEK293 cells transfected with the human 5-HT6 receptor.
Cells were treated with the indicated concentrations of 5-HT
(O), or compound 7 in the presence of 1 nM 5-HT (2), 3 nM
5-HT (9), or 10 nM 5-HT (*). Data points represent the mean
of duplicate determinations from a typical experiment that was
repeated at least twice.
Ta ble 2. 5-HT6 Receptor Binding Affinity Data
compd
IC50 (nM)a
compd
IC50 (nM)a
1
7
13
15
16
26.3 ( 7.5
4 ( 0.8
17
18
19
20
269 ( 89
68.9 ( 11
79.2 ( 14.5
3580 ( 80
524 ( 47
87.6 ( 21.2
70.1 ( 11.2
a
Concentration required to inhibit 50% [3H]LSD binding. These
values are the mean ( SEM (n ) 2-6).
F igu r e 3. Schild analysis of 7. 5-HT EC50 values were
determined in the absence or presence of increasing concentra-
tions of 7 and dose ratios were calculated by dividing the EC50
values determined in the presence of 7 with the EC50 deter-
mined for 5-HT alone. The linear transformation of the data
plotting the log (dose ratio - 1) vs -log[compound 7] yielded
a slope of -0.95 with an X intercept of 8.4. Data points
represent the mean of triplicate determinations from a typical
experiment that was repeated at least twice.
Ta ble 1. Human Cytochrome P450 Inhibitory Data of 7
CYP isoform
IC50 (µM)a
1A2
2C9
2C19
>40
24.2 ( 8.35
0.86 ( 0.27
F igu r e 4. Overlap of Ro 04-6790 (1, red) and SB-271046 (3,
blue) onto crystal structure of 7 (green) with sulfur atoms
colored yellow.
2D6
>40
>40
>40
3A4-BFCb
3A4-BzResc
a
IC50 values were determined for inhibition of deethylation of
(Table 2). Dramatic reduction in binding affinity was
observed with 2-methyl-4-bromo disubstitution (i.e., 17,
IC50 269 nM). It is interesting to note that both the
isoquinolinyl analogue 18 and 2-naphthyl analogue 19
still maintained moderate binding affinity (IC50 68.9 and
79.2 nM, respectively). Replacement of the phenyl group
in 7 with alkyl groups such as n-propyl (i.e., 20) removed
binding activity (IC50 3.6 µM). This suggests that the
phenyl group of 7 may play a critical role in the
interaction with 5-HT6 receptors. Finally, it is worth
noting that the uncyclized product 13 (Scheme 3)
exhibited weak binding activity (IC50 524 nM) presum-
ably due to the lack of a cyclized amidine functionality
as shown in 7.
3-cyano-7-ethoxycoumarin (CYP1A2 and CYP2C19), for dealkyl-
ation of 7-methoxy-4-trifluoromethylcoumarin (CYP2C9), and for
inhibition of demethylation of 3-[2-(N,N-diethyl-N-methylamino-
)ethyl]-7-methoxy-4-methylcoumarin (CYP2D6). Two different
substrates were used to determine the IC50 values for CYP3A4;
the inhibition of dealkylation of BzRes (benzoylresorufin) and of
BFC (7-benzyloxy-4-trifluoromethylcoumarin). These values are
the mean ( SEM (n ) 7). b BFC was used as the substrate. c BzRes
was used as the substrate.
CYP2C19, CYP2D6, and CYP3A4 (Table 1) in order to
assess the potential likelihood of drug interactions. Low
to moderate levels of inhibition were observed at several
major human P450 enzymes with the highest level of
inhibition against CYP2C19 (IC50 0.86 µM).
Preliminary structure-activity relationship studies
on 7 have been carried out. Thus, both fluoro substitu-
tion at C2 of pyridinylidene moiety (i.e., 15, Chart 2)
and ethyl substitution at C3 (i.e., 16) reduced the
binding affinity by about 22- and 18-fold, respectively
Molecular modeling overlays of the X-ray structure
of 7 were performed with compounds 1 and 3, using
Sybyl’s superimposition algorithm.28 The sulfur atoms
of the arylsulfonyl groups were marked to be coincident
but the reminder of the molecule was left to find the

Letters
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 23 4837
(12) Sleight, A. J .; Boess, F. G.; Bos, M.; Levet-Trafit, B.; Riemer,
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structure of 7 (Figure 4). This suggests that these
compounds may all bind in the same fashion to the
5-HT6 receptors.
Con clu sion . Compound 7 was identified as a potent
and selective 5-HT6 antagonist, and a one-step synthesis
has been developed. This compound represents a dis-
tinct novel chemotype of 5-HT6 ligands and is expected
to be a useful tool for further pharmacological evaluation
of the function of the 5-HT6 receptors. Future efforts
are directed at improving both cytochrome P450 inhibi-
tion profiles and metabolic stability of 7.
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Amide
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Ack n ow led gm en t. We thank Dr. J oanne Bronson
for helpful discussions and critical reading of the
manuscript.
Su p p or tin g In for m a tion Ava ila ble: Experimental sec-
tion containing the synthesis of 7, 13, and 15-20, 5-HT6
receptor Ca2+ flux assay, and a brief computational methodol-
ogy section. This material is available free of charge via the
Internet at http:/pubs.acs.org.
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