Novel potent antagonists of human neuropeptide Y Y5 receptors. Part 2: Substituted benzo[a]cycloheptene derivatives

Article abstract of DOI:10.1016/S0960-894X(02)00002-1

Novel benzo[a]cycloheptene derivatives were prepared for the purpose of searching new neuropeptide Y-Y5 (NPY-Y5) receptor antagonists. The structure-activity relationships are described and compound 2o (FR226928) showed the most potent affinity for Y5 receptor of all we prepared and was found to have higher potency and better selectivity for Y5 over Y1 receptor affinities when compared with the known lead compound 1.

Full text of DOI:10.1016/S0960-894X(02)00002-1

Bioorganic & Medicinal Chemistry Letters 12 (2002) 757–761
Novel Potent Antagonists of Human Neuropeptide Y Y5
Receptors. Part 2: Substituted Benzo[a]cycloheptene Derivatives
Hiromichi Itani,a Harunobu Ito,b Yoshihiko Sakata,b Yoshifumi Hatakeyama,b
Hiroko Oohashib and Yoshinari Satoha,*
aMedicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa-ku, Osaka 532-8514, Japan
bMedicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa-ku, Osaka 532-8514, Japan
Received 26 October 2001; accepted 14 December 2001
Abstract—Novel benzo[a]cycloheptene derivatives were prepared for the purpose of searching new neuropeptide Y-Y5 (NPY-Y5)
receptor antagonists. The structure–activity relationships are described and compound 2o (FR226928) showed the most potent
affinity for Y5 receptor of all we prepared and was found to have higher potency and better selectivity for Y5 over Y1 receptor
affinities when compared with the known lead compound 1. # 2002 Elsevier Science Ltd. All rights reserved.
Obesity is now a major health problem in advanced
nations and even mild obesity enhances the risk of pre-
mature death, hypertension, diabetes mellitus, hyper-
severe overeating leading to the development of obe-
sity.9 There are at least five different NPY receptor
subtypes (Y1, Y2, Y4, Y5 and Y6), which are recog-
nized as members of the superfamily of G-protein cou-
pled receptors. The existence of a Y3 subtype receptor
has been supported by substantial pharmacological evi-
dence but it has not yet been cloned. The Y1 and/or Y5
receptor subtypes are activated according to centrally-
mediated NPY-induced feeding responses.14ꢀ17 It has
been reported that compounds which antagonize the Y5
receptor, for example, CGP71683A,18 are significantly
effective in reducing food intake in ob/ob mice and
Zucker obese rat models.19 Furthermore, potent com-
pounds, which contain a- or b-naphthalenesulfonamide
as a substructure (e.g., 1) were disclosed recently (Fig.
1).20
lipidaemia, atherosclerosis, coronary heart disease,
1,2
arthritis, sleepapnea and certain types of cancer.
A
strong association between obesity and non-insulin
dependent diabetes mellitus (NIDDM) has been
claimed, and more than 80% of NIDDM patients are
known to be clinically obese.3
Neuropeptide Y (NPY) is a 36 amino acid peptide that
was first isolated from porcine brain4 and is found
abundantly in the central and peripheral nervous sys-
tem.5,6 NPY is said to have a relation to a number of
physiological responses, such as food intake,7ꢀ9 blood
pressure regulation,10,11 hormone secretion,12 sexual
behavior,13 and circadian rhythm10 and is implicated in
the pathophysiology of several disorders. It has been
reported that chronic injection of NPY in rats lead to
Consequently, we attempted to discover a novel com-
pound that possesses Y5 receptor antagonistic activity
Figure 1.
*Corresponding author. Tel.: +81-6-6390-1376; fax: +81-6-6304-5435; e-mail: yoshinari_satoh@po.fijisawa.co.jp
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00002-1

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H. Itani et al. / Bioorg. Med. Chem. Lett. 12 (2002) 757–761
by using these lead compounds for the treatment of
obesity and eating disorders. We speculated that the
naphthalenesulfonamide moiety was essential for affi-
nity to the Y5 receptor and the trans-cyclohexyl group
was exchangable into a piperizine ring. Instead of the
aminoquinazoline and the tetralin nuclei, we selected a
substituted benzo[a]cycloheptene ring as a key pharma-
cophore, because it is also used in b3-adrenoceptor
agonists and is present in FK175, a candidate discovered
in another research team,21 in an attempt to identify a
compound with dual character as an NPY-Y5 receptor
antagonist and a b3-adrenoceptor agonist.
This paper describes the synthesis of novel benzo[a]-
cycloheptene derivatives as NPY-Y5 receptor antago-
nists and their structure–activity relationships (Fig. 2).
Initially, we prepared racemic compound 2 by the route
shown in Scheme 1. Compound 2 showed a moderate
affinity for Y5 receptors (IC50=7.4ꢁ10ꢀ7 M) and
poor affinity for Y1 receptors (IC50=1.9ꢁ10ꢀ5 M).
This prompted us to synthesize other related com-
pounds to obtain more potent and selective deriva-
tives.
We first exchanged the position of the methoxy group
on the benzo[a]cycloheptene ring, the alkyl spacer
length and the binding positions to the piperidine ring.
Compounds 2a and 2b were prepared according to
similar methods to that carried out in the preparation of
2. 2c and 2d were obtained by reductive amination of
aldehyde 21 and ketone 6, as shown in Scheme 2, with
the respective amines 22 and 24, which were prepared
by general methods as shown in Scheme 3. They are
Figure 2.
Scheme 1. Reagents and conditions: (a) Me3SiCN, cat Znl2; (b) LiAlH4; (c) aq NaNO2; (d) C6H5CH2NH2, NaBH(OAc)3; (e) BrCH2CO2Et, K2CO3;
(f) aq NaOH; (g) Boc2O, Et3N; (h) aq NaOH; (i) CICOO-i-Bu, N-methylmorpholine; aq NH3; (j) LiAlH4; (k) a-naph-SO2Cl, Et3N; (l) 4N-HCl-
AcOET; (m) WSC, HOBT; (n) HCOONH4, Pd/C; (o) LiAlH4; (p ) 4N-HCl–AcOEt.
Scheme 2. Reagents and conditions: (a) Ph3P¼CHOCH3; (b) 6N-HCl; (c) NaBH(OAc)3, cat AcOH.

H. Itani et al. / Bioorg. Med. Chem. Lett. 12 (2002) 757–761
759
Scheme 3. Reagents and conditions: (a) BrCH2CO2Et, Et3N; (b) aq NaOHl; (c) ClCOO-i-Bu, N-methylmorpholine; aq NH3; (d) LiAlH4; (e) Boc2O,
Et3N; (f) 4N-HCl-AcOEt; (g) N-bromoethylphthalimide, Et3N; (h) NH2NH2 H2O; (i) naphthalenesulfonyl chloride, Et3N; (j) LiAlH4.
Table 1. Y5 and Y1 receptor affinities of compounds 2 and 2a–d
Compda
Position of –OCH3
m
n
Bond A to
piperidine
Bond B to
piperidine
p
Binding affinity (IC50)
Y5b
Y1c
1d
3.8ꢁ10ꢀ8 M
1.3ꢁ10ꢀ6 M
2
3
2
1
3
3
0
0
0
1
0
2
2
2
2
1
10
10
10
10
40
40
40
40
40
10
1
1
1
1
2
7.4ꢁ10ꢀ7 M
1.0ꢁ10ꢀ6 M
>1.0ꢁ10ꢀ6 M
5.4ꢁ10ꢀ7 M
4.5ꢁ10ꢀ8 M
1.9ꢁ10ꢀ5 M
2a
2b
2c
2d
—
—
2.8ꢁ10ꢀ6 M
1.4ꢁ10ꢀ5 M
aCompound is a racemic mixture.
bConcentration of compound that inhibited 50% of total specific binding of 125I-PYY as a ligand to human NPY-Y5 receptors.
cConcentration of compound that inhibited 50% of total specific binding of 125I-PYY to human NPY-Y1 receptors.
dLead compound 1.
Table 2. Substituent effects on Y5 and Y1 receptor affinities
summarized in Table 1 accompanied by the biological
evaluation results of them and the lead compound 1.
The best position for the methoxy moiety was found to
be the 3-position of the benzo[a]cycloheptene ring, and
the optimum length of spacer, that is, m+n+p, was
found to be 3. Furthermore, it is also found that com-
pound 2d, whose bond-A binds to the 40-position of
piperidine ring, was more potent than the other com-
pounds. We next changed the methoxy group of 2d
into other kinds of substituents leaving other parts of
the structure unchanged. These compounds were syn-
thesized according to similar methods to that carried
out in the preparation of 2d and are summarized in
Table 2.
Compda
R
Binding affinity (IC50)
Y5b
Y1c
2d
3-OCH3
4.5ꢁ10ꢀ8 M
1.4ꢁ10ꢀ5 M
2e
2f
2g
2h
2i
2j
2k
2l
H
2,3-di-OCH3
3-Cl
3-CH3
3-NO2
3-NH2
3-OCH2CO2C2H5
3-OCH2CO2H
2.1ꢁ10ꢀ7 M
6.8ꢁ10ꢀ8 M
8.5ꢁ10ꢀ8 M
7.2ꢁ10ꢀ8 M
7.9ꢁ10ꢀ8 M
5.2ꢁ10ꢀ8 M
6.8ꢁ10ꢀ7 M
25.7% (at 10ꢀ6 M)
—
1.7ꢁ10ꢀ5 M
8.5ꢁ10ꢀ6 M
1.8ꢁ10ꢀ5 M
1.5ꢁ10ꢀ5 M
—
—
—
The kind of 3-substituents was found not to be so
important for increasing the potencies and 2d showed
the most potent affinity in this series. Next, we changed
the alkyl spacer length between the benzo[a]cyclo-
heptene and piperidine rings. The evaluation results are
summarized in Table 3.
aCompound is a racemic mixture.
bConcentration of compound that inhibited 50% of total specific
binding of 125I-PYY as a ligand to human NPY-Y5 receptors.
cConcentration of compound that inhibited 50% of total specific
binding of 125I-PYY to human NPY-Y1 receptors.

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H. Itani et al. / Bioorg. Med. Chem. Lett. 12 (2002) 757–761
As shown in Table 3, the order of potency as Y5 recep-
tor antagonists was 2o>2n>2d>2m, though we con-
sider there is no significant difference in terms of
pharmacological effect.
stituent on the benzo[a]cycloheptene ring compared to
3,4-di-methoxy, 3-chloro- and 3-methyl groups.
Summary
Considering the above results, we next synthesized rela-
ted compounds by changing the piperidine part into
other aliphatic heterocyclic rings. We selected an azeti-
dine ring instead of piperidine because of its easy avail-
ability and lack of an asymmetric carbon. N-[2-(3-
Aminomethylazetidin-1-yl)ethyl]-1-naphthalenesulfon-
amide was synthesized by similar methods to that
carried out in the preparation of piperidine derivative
24. The structures and evaluation results are summar-
ized in Table 4.
We synthesized many novel substituted benzo[a]cyclo-
heptene derivatives based on the idea that lead com-
pound 1 as an NPY-Y5 antagonist might lead to an
ideal anti-obesity drug if it possessed the b3-adreno-
ceptor agonistic character of FK175, which contains a
benzo[a]cycloheptene ring in its structure. Compound
2o (FR226928) showed the most potent affinity
(IC50=1.6ꢁ10ꢀ8 M) for the NPY-Y5 receptor of all
compounds we prepared, and it was found to have
higher potency and better selectivity for Y5 over Y1
receptor affinities than the lead compound 1. Never-
theless, it was not enough from the viewpoint of
potency and brain permeability. This derivative is
undergoing further biological evaluation to determine
whether the b3-adrenoceptor agonistic character is pre-
sent in addition to its NPY-Y5 antagonistic activity or
not. We are continuing our search for improved deriva-
tives.
It was found that an azetidine ring had a similar effect
to that of the piperidine ring, but was slightly weaker.
When the piperidine ring was replaced by azetidine, the
3-methoxy moiety was also more suitable as a sub-
Table 3. Effects of the spacer alkyl length
Acknowledgements
Compda
m
n
Binding affinity (IC50)
The authors would like to acknowledge Dr. D. Barrett
for helpful discussions and critical reading of the
manuscript.
Y5b
Y1c
2d
0
1
4.5ꢁ10ꢀ8 M
1.4ꢁ10ꢀ5 M
2m
2n
2o
0
1
1
0
0
1
6.6ꢁ10ꢀ8 M
3.9ꢁ10ꢀ8 M
1.6ꢁ10ꢀ8 M
3.5ꢁ10ꢀ5 M
2.9ꢁ10ꢀ5 M
9.6ꢁ10ꢀ6 M
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1d
3.8ꢁ10ꢀ8 M
1.3ꢁ10ꢀ6 M
aCompound is a racemic mixture.
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3-CH3
1d
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aCompound is a racemic mixture.
bConcentration of compound that inhibited 50% of total specific
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cConcentration of compound that inhibited 50% of total specific
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dLead compound 1.

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