Novel Potent Antagonists of Human Neuropeptide Y Y5 Receptors. Part 3: 7-Methoxy-1-hydroxy-1-substituted Tetraline Derivatives

Article abstract of DOI:10.1016/S0960-894X(02)00018-5

As a part of our continuing research on NPY-Y5 receptor antagonists in the series of novel 6-methoxybenzo[a]cycloheptene derivatives, we discovered a novel skeleton, 7-methoxy-1-hydroxytetraline 7 which had been used as an intermediate, to be more suitable for increasing potencies leading to compound 3 (FR230481). Additionally, we discovered that the naphthalenesulfonamide moiety which was thought to be an essential pharmacophore could be replaced by the 5-chlorobenzothiazolin-3-acetic acid moiety to lead to potent compound 4 (FR233118). The structure-activity relationships on compounds 3, 4 and their related derivatives are described. Unfortunately, although compounds 3 and 4 had very high affinities for Y5 receptors, their poor permeabilities to brain were shown by exo-vivo binding assays when orally administered.

Full text of DOI:10.1016/S0960-894X(02)00018-5

Bioorganic & Medicinal Chemistry Letters 12 (2002) 799–802
Novel Potent Antagonists of Human Neuropeptide Y Y5
Receptors. Part 3: 7-Methoxy-1-hydroxy-1-substituted
Tetraline 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 21 November 2001; accepted 27 December 2001
Abstract—As a part of our continuing research on NPY-Y5 receptor antagonists in the series of novel 6-methoxy-
benzo[a]cycloheptene derivatives, we discovered a novel skeleton, 7-methoxy-1-hydroxytetraline 7 which had been used as an
intermediate, to be more suitable for increasing potencies leading to compound 3 (FR230481). Additionally, we discovered that the
naphthalenesulfonamide moiety which was thought to be an essential pharmacophore could be replaced by the 5-chlorobenzo-
thiazolin-3-acetic acid moiety to lead to potent compound 4 (FR233118). The structure–activity relationships on compounds 3, 4
and their related derivatives are described. Unfortunately, although compounds 3 and 4 had very high affinities for Y5 receptors,
their poor permeabilities to brain were shown by exo-vivo binding assays when orally administered. # 2002 Elsevier Science Ltd.
All rights reserved.
Neuropeptide Y (NPY) is a 36 amino acid peptide that
was first isolated from porcine brain1 and is said to have
a relation to food intake.2À4 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.5 It has been reported that chronic injection of
NPY in rats lead to severe overeating leading to the
development of obesity.4 The Y1 and/or Y5 receptor
subtypes amongst the already cloned five different sub-
types are activated according to centrally-mediated
NPY-induced feeding responses.6À9 Furthermore, it
has been reported that compounds which antagonize the
Y5 receptor (e.g., CGP71683A10 or compound 1) are
significantly effective in reducing food intake in ob/ob
mice and Zucker obese rat models.11 Consequently, we
attempted to discover a novel compound that possesses
Y5 receptor antagonistic activity for the treatment of
obesity and eating disorders (Fig. 1).
We reported in a previous paper12 that novel 8-meth-
oxybenzo[a]cycloheptene derivative 2 (FR226928), was a
potent Y5 receptor antagonist. We have continued our
search for improved derivatives because of dissatisfac-
tion from the viewpoint of potency and brain perme-
ability. We succeeded in discovering 3 (FR230481), and
4 (FR233118), which showed increased activity (about
20-fold relative to 2) (Fig. 2). This letter describes the
synthesis and structure–activity relationships of these
analogues.
We discovered 3 using serendipity, by employing a
novel skeleton, 7-methoxy-1-aminomethyl-1-hydroxy-
tetraline 7, which was used as an intermediate in the
preparation of 2 described previously.12 7 was easily
condensed with 8, prepared by general methods, by
reductive amination reactions in the presence of sodium
borotriacetoxyhydride and a catalytic amount of acetic
acid in methylene chloride, as shown in Scheme 1.
Surprisingly, compound 3 exhibited very potent affinity
for the Y5 receptor, hence we next prepared related
compounds with larger and smaller rings than a tetra-
line ring (3a and 3b), modified length of spacer (3c) and
*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)00018-5

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H. Itani et al. / Bioorg. Med. Chem. Lett. 12 (2002) 799–802
Scheme 1. Reagents and conditions: (a) (CH3)3SiCN, cat Zn12; (b) LiAIH4 (c) phthalimide-N-acetic acid, HOBT, WSC; (d) hydrazine hydrate; (e) a-
naphthalenesulfonyl chloride, Et3N; (f) MnO2; (g) NaBH(OAc)3.
exchanged the naphthalenesulfonamide into various
substituted phenyl sulfonamides (3d and 3e). These
analogues were synthesized according to similar meth-
ods to that carried out in the preparation of 3, and are
summarized in Table 1 accompanied by the IC50 values
for human Y5 receptor binding.
n=2. The naphthalene ring of compound 3 was found
to be the most suitable, because compounds 3d and 3e
containing the substituted phenyl ring instead of the
naphthalene ring were decreased in their affinities to one
twentieth when compared with 3.
Compound 9 (Fig. 3) was discovered by screening of
our in-house chemical library as a comparable potent
(IC50=53 nM) NPY-Y5 receptor antagonist. We have
prepared many kinds of derivatives developed from its
novel and unique structure by parallel synthesis techni-
que in a previously reported paper.13 We considered
that a part of this structure, 5-chloro-2-oxobenzothia-
The tetraline ring was found to be the most suitable ring
in this series. Both the ring-enlarged 3a and ring-con-
tracted 3b showed only about one hundredth the
potency when compared with 3. When comparing 3c
with 3, it was found that there is also a proper spacer
length in this series, and n=1 is more suitable than
Figure 1.
Figure 2.
Figure 3.
Figure 4.

H. Itani et al. / Bioorg. Med. Chem. Lett. 12 (2002) 799–802
801
Scheme 2. Reagents and conditions: (a) NaNO2; (b) PhCH2NH2, NaBH(OAc)3; (c) H2, Pd/C; (d) ethyl isonipecotate, WSC HCI, HOBT, Et3N; (e)
aq NaOH; (f) BH3 Me2S; (g) MnO2; (h) NaBH(OAc)3.
zoline, could be used instead of naphthalene moiety of
compound 3.
by reduction of 15 with borane dimethylsulfide, respec-
tively. The structures and the evaluation results of these
compounds are summarized in Table 2.
Compound 4 and its related compounds (4a–4c) were
prepared as shown in Scheme 2.
It was found that all of these compounds were as potent
as compound 3, that is to say that the 5-chloro-2-oxo-
benzothiazolin-3-acetic acid moiety could be used as a
bioisoster of a naphthalene alkylsulfonamide group in
this series. Compound 4 showed not only about 20-fold
potency for Y5 receptors than compound 2, but also
high selectivity for Y5 over Y1 receptors as shown in
Figure 2. It was very interesting that 4b and 4c showed
high affinities for Y5 receptors although they have no
basic part in their structure, in contrast to compound 3.
Nevertheless, 4b and 4c had been dramatically
decreased in their water solubilities due to the two
The intermediate amine 12 was obtained by hydro-
genolysis of compound 11, prepared by reductive ami-
nation with benzylamine of ketone 10, which was
prepared by diazotization of compound 6 with sodium
nitrite followed by ring expansion reaction. The inter-
mediate carboxylic acid 15 was obtained by alkali
hydrolysis of amidated product 14 with ethyl iso-
nipecotinate, and the aldehyde 17 was prepared by
manganese oxidation of alcohol 16, which was obtained
Table 1. Y5 receptor affinities of compounds 3 and 3a–e
Table 2. Evaluation results on binding affinities for NPY Y5 receptor
of 4 and 4a–c
Compda
R1
n
R2
IC50 (nM)b
0.54
3
1
Compda
R
IC50 (nM)b
3a
3b
3c
3d
3e
1
1
2
1
1
56
66
24
13
11
4
0.7
4a
4b
4c
28
1.0
1.2
aCompound is a racemic mixture.
aCompound is a racemic mixture.
bConcentration of compound that inhibited 50% of total specific
binding of 125 I-PYY as a ligand to the human NPY-Y5 receptors;
obtained from mean value of twice experiments at each concentration
(10À6 – 10À10 M).
bConcentration of compound that inhibited 50% of total specific
binding of 125 I-PYY as a ligand to the human NPY-Y5 receptors;
obtained from mean value of twice experiments at each concentration
(10À6 – 10À10 M).

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H. Itani et al. / Bioorg. Med. Chem. Lett. 12 (2002) 799–802
amides moieties. Accordingly, we tried again to intro-
duce a naphthalenesulfonamide group into compound
4. We designed 4d, as shown in Figure 4, in which the
basicity of the piperidine ring was removed by amide
formation and the other basic amine was left untouched
in order to be able to form a salt. 4d exhibited potent
affinity (3.7 nM) for NPY Y5 receptors as was expected.
Acknowledgements
We would like to thank Dr. D. Barrett for helpful dis-
cussions and critical reading of the manuscript.
References and Notes
Unfortunately, although the compounds described in
this paper possessed potent affinities for NPY Y5
receptors, their poor permeabilities to brain were shown
by exo-vivo binding assays when orally administered at
100 mg/kg to rats.
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As a part of our continuing research on NPY-Y5
receptor antagonists in the series of novel 8-methoxy-
benzo[a]cycloheptene derivatives, we discovered
novel skeleton, 7-methoxy-1-hydroxytetraline 7 which
a
had been used as an intermediate, to be more suitable
for increasing potencies leading to compound
3
(FR230481). This compound showed 30-fold more
potent affinity for Y5 receptors when compared with 2
(FR226928), the most potent compound in the pre-
viously reported series.12 Additionally, we discovered
that the naphthalenesulfonamide moiety which was
thought to be an essential pharmacophore could be
replaced by the 5- chlorobenzothiazolin-3-acetic acid
moiety to lead to compound 4 (FR233118) exhibiting
about 20-fold more potent activity than 2.
Unfortunately, although compounds 3 and 4 had very
high affinities for Y5 receptors, their poor permeabilities
to brain were shown by exo-vivo binding assays when
orally administered at 100 mg/kg to rats, and we are
continuing our search for improved compounds.