Bicyclo[2.2.1]heptane and 6,6-dimethylbicyclo[3.1.1]heptane derivatives: Orally active, potent, and selective prostaglandin D2 receptor antagonists

Full text of DOI:10.1021/jm970343g

3504
J . Med. Chem. 1997, 40, 3504-3507
Bicyclo[2.2.1]h ep ta n e a n d
6,6-Dim eth ylbicyclo[3.1.1]h ep ta n e
Der iva tives: Or a lly Active, P oten t, a n d
Selective P r osta gla n d in D2 Recep tor
An ta gon ists
F igu r e 1.
Ta ble 1. Inhibition of DP, TP, and IP Receptor Binding and
Biological Activity in Human Platelets
Tatsuo Tsuri,* Tsunetoshi Honma,
IC50 (µM)a-c
Yoshiharu Hiramatsu, Toshihiko Okada,
Hiroshi Hashizume, Susumu Mitsumori,
Masanao Inagaki, Akinori Arimura, Kiyoshi Yasui,
Fujio Asanuma, J unji Kishino, and Mitsuaki Ohtani*
DP
TP:
binding
IP:
cAMP
compd
binding
cAMP
(+)-1
(-)-1
(+)-3
(-)-3
4
0.60
0.46
1.2
4.9
0.45
0.52
0.42
1.1
5.0
>10
8.9
0.044
0.67
0.00013
1.3
1.3
0.28
1.7
Shionogi Research Laboratories, Shionogi & Co., Ltd.,
Fukushima-ku, Osaka 553, J apan
>1
3.3
0.72
0.78
0.32
0.25
0.070
0.25
0.068
>10
>10
>10
1.5
Received May 23, 1997
5
6
7
8
0.027
0.0086
0.13
1.1
0.027
3.0
0.047
5.2
1.6
0.032
0.032
0.00040
0.00027
0.0013
0.026
0.54
Prostaglandin D2 (PGD2), the major cyclooxygenase
metabolite produced by mast cells in response to IgE-
dependent stimuli,1 has a variety of inflammatory
effects.2 PGD2 is considered to be an important media-
tor in various allergic diseases such as allergic rhinitis,
atopic asthma, allergic conjunctivitis, and atopic der-
matitis. However, only one compound is available as a
tool for pharmacological examination of the PGD2 recep-
tor,3 and there has been no report on the efficacy of
PGD2 receptor antagonists in animal allergic models or
against human allergic diseases. We thought that a
selective PGD2 receptor antagonist may be of therapeu-
tic value for various allergic disorders.
Our attempt to develop PGD2 receptor antagonists
was undertaken upon discovery of a lead compound by
screening of our compound library for their inhibitory
effects on specific [3H]PGD2 binding to human platelet
membranes. We found that (()-(5Z)-7-[3-[(biphenyl-4-
ylsulfonyl)amino]bicyclo[2.2.1]hept-2-yl]hept-5-enoic acid
(1), previously reported to be a thromboxane A2 (TXA2)
receptor antagonist,4 exhibited fairly strong binding to
PGD2 receptor (Figure 1). We synthesized the two
enantiomers of this compound to determine their bio-
logical activities. A comparison of (+)-1 and 3 with their
(-)-enantiomers revealed that the (+)-enantiomers were
suitable for our purpose, since the (-)-enantiomers
exhibited strong TXA2 receptor binding activity and no
effect on nasal blockage in the in vivo model (Tables 1
and 2). Next, a structure-activity relationship study
was performed with bicyclic ring systems and ω-side
chains. Since these studies revealed that the 6,6-
dimethylbicyclo[3.1.1]heptane ring system was also
effective for inhibiting PGD2 binding, two different types
of structures were synthesized to obtain the desired
compounds.
4.5
5.9
1.4
9
>10
10
13
15
16
17
18
19
20
21
22
23
24
25
26
>1
0.12
0.36
1.2
0.81
2.1
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
7.5
0.038
0.064
0.022
0.0010
0.0018
0.0028
0.0056
0.38
3.1
0.38
0.096
0.43
0.41
0.21
0.15
0.27
0.74
0.24
0.032
1.3
0.78
0.22
>1
>1
3.4
>10
a
PGD2 receptor (DP) assay. Inhibition of [3H]PGD2 specific
binding to human platelet membranes9 and cAMP formation
evoked by PGD2 in human platelets.10 The human platelet
membranes were incubated with various concentrations of the test
compounds and 5 nM [3H]PGD2 for 60 min at 4 °C. Human
platelets were stimulated with 0.1 µM PGD2 for 2 min following
10-min preincubation with various concentrations of the test
compounds at 37 °C in the presence of 3-isobutyl-1-methylxanthine
b
(IBMX). TXA2 receptor (TP) assay. Inhibition of [3H](+)-S-145
specific binding to human platelet membranes.11 The human
platelet membranes were incubated with various concentrations
of the test compounds and 2 nM [3H](+)-S-145 for 60 min at room
temperature. c PGI2 receptor (IP) assay. Inhibition of cAMP forma-
tion by carbacyclin.10 Human platelets were incubated with 0.1
µM carbacyclin for 2 min following 10-min preincubation with
various concentrations of the test compounds at 37 °C in the
presence of IBMX. IC50 represents the mean value of two or three
measurements.
11 by the Sonogashira reaction,7 followed by Pd-
catalyzed cyclization reaction (Scheme 2).8
Biologica l Resu lts a n d Discu ssion
The structure-activity relationship study revealed
that, for exhibition of the potent antagonism of the PGD2
receptor, sulfonylamino and carbonylamino groups are
required for the compounds with bicyclo[2.2.1]heptane
ring and 6,6-dimethylbicyclo[3.1.1]heptane ring sys-
tems, respectively. In the case of compounds with a
bicyclo[2.2.1]heptane ring system, phenyl- or biphenyl-
ylsulfonylamino derivatives having various substituents
did not show improved activity. Since the conformation
of the biphenyl ring seemed to be important, we
prepared some compounds having a spacer between the
two phenyl rings of 1 to change their conformation. Good
activity was obtained as illustrated by compounds 4-6
Ch em istr y
(1S,2R,3R,4R)-(5Z)-7-(3-Aminobicyclo[2.2.1]hept-2-yl)-
hept-5-enoic acid methyl ester and (1R,2R,3S,5S)-(5Z)-
7-(2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)hept-5-
enoic acid methyl ester were prepared by methods
described in the literature.4,5 Coupling these amino
derivatives with sulfonyl chloride or carbonyl chloride
prepared by conventional methods readily produced the
desired esters in good yield.6 Hydrolysis of these esters
using aqueous potassium hydroxide in methanol pro-
duced the target molecules in almost quantitative yields
(Schemes 1 and 3). Compound 13 was obtained from
S0022-2623(97)00343-9 CCC: $14.00 © 1997 American Chemical Society

Communications to the Editor
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 22 3505
Sch em e 2a
Ta ble 2. Inhibition of Antigen-Induced Nasal Blockage in
Guinea Pigs
rhinitis model
compd
% inhibn at 1 mg/kg (iv)a
ED50 (mg/kg, po)b
(+)-1
(-)-1
(+)-3
(-)-3
4
6
7
9
13
39 ( 17c
-20 ( 24c
54 ( 9d
6 ( 24
25 ( 9
25 ( 12
82 ( 4d
80 ( 3d
60 ( 7d
77 ( 5d
78 ( 8d
3.5e
2.2
7.2
5.1
2.1
1.0
16
19
20
a
Inhibition of antigen-induced increase in intranasal pressure
in actively sensitized guinea pigs, according to ref 12. Compounds
were administered iv 10 min before the antigen challenge. Values
b
are the mean ( SEM; n ) 5-10/group. Dose required to inhibit
a
Reagents: (a) RSO2Cl, Et3N; (b) Pd(PPh3)2Cl2, phenylacety-
lene; (c) Fe, NH4Cl; (d) PdCl2; (e) KOH.
50% of antigen-induced increase in intranasal pressure. Com-
pounds were administered po 1 h before the challenge. Dose-
response data was determined for n ) 5-10 animals/data point.
Sch em e 3a
d
c Tested at 3 mg/kg. Significantly different from each control, p
< 0.01 (Student’s t-test). e Na salt was used.13
Sch em e 1a
a
Reagents: (a) RSO2Cl, Et3N; (b) KOH; (c) RCOCl, Et3N.
a
Reagents: (a) RCOCl, Et3N; (b) KOH; (c) RSO2Cl, Et3N.
(Table 1). The same was attempted with compounds
having carbonylamino groups, but no improved activity
was observed as shown by compound 10. Next, we
linked each phenyl group of 4 by a C-C bond to make
a rigid conformation of diphenyl ether group. This
attempt enhanced in vivo activity, as illustrated by
compound 7 (Table 2). A similar modification was
performed for compound 6. The corresponding com-
pound 13 also exhibited in vivo activity higher than did
6. Various kinds of substituents were tested for com-
pound 7, and introduction of an electron-donating group
to the aromatic ring systems resulted in higher in vitro
activities, as demonstrated by comparison of compounds
7, 8, and 9.
On the other hand, in the case of compounds with a
6,6-dimethylbicyclo[3.1.1]heptane ring system, carbo-
nylamino groups gave better activity than sulfonylamino
groups in the in vitro assay, as demonstrated by
comparison of compounds 23, 24, 25, and 26. Among
the compounds having carbonylamino groups, the simple
compound 15 exhibited fairly good activity, and replac-
ing the phenyl group with a thiophene group enhanced
the activities in both assays as shown by compound 16.
Further modification of this moiety, mainly by replace-
ment with heterocyclic aromatic rings, was performed
to obtain the highly active compounds 17-22.
Further evaluation was performed for the selected
compounds 9, 16, 19, and 20, which markedly inhibited

3506 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 22
Communications to the Editor
Ta ble 3. Effect of Orally Administered DP Antagonists on
PGD2- and Antigen-Induced Increase in Vascular Permeability
in Conjunctiva and Antigen-Induced Increase in Specific
Airway Resistance in Guinea Pigs
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails with spectral data (20 pages). Ordering information is
given on any current masthead page.
conjunctivitis model
asthma model
Refer en ces
ED50 (mg/kg)a
% inhibn at 10 mg/kg:b
(1) Lewis, R. A.; Soter, N. A.; Diamond, P. T.; Austen, K. F.; Oates,
J . A.; Roberts, L. J ., II. Prostaglandin D2 generation after
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Immunol. 1982, 129, 1627-1631.
compd
PGD2
antigen
antigen
9
16
19
20
1.6
3.5
0.12
3.5
6.6
9.5
2.0
8.9
42 ( 12
15 ( 21
70 ( 5c
69 ( 9c
(2) (a) Flower, R. J .; Harvey, E. A.; Kingston, W. P. Inflammatory
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a
Dose required to inhibit 50% of the increase in conjunctival
microvascular permeability caused by topical application of 0.1%
PGD2 in normal guinea pigs2d or antigen in guinea pigs which
actively sensitized with ovalbumin.12 Dose-response data was
b
determined for n ) 3-10 animals/data points. Inhibition of
increase in specific airway resistance by antigen inhalation in
conscious guinea pigs. All antagonists were administered po 1 h
before the challenge. Values represent the mean ( SEM, n ) 4-11
animals/group. c Significantly different from each control, p < 0.01
(Student’s t-test).
PGD2- and antigen-induced increase in conjunctival
microvascular permeability. In the asthma model, these
compounds, particularly 19 and 20, also inhibited an
antigen-induced increase in specific airway resistance
at 10 mg/kg (po) (Table 3). Since PGD2 is thought to
exert a contractile response of airway smooth muscle
by directly acting on the TXA2 receptor not via the PGD2
receptor,3a,14,15 there is a possibility that the antiasth-
matic activity of these compounds arose from their TXA2
receptor antagonistic activity. However, this possibility
was ruled out by our finding that all four of these
compounds did not meaningfully affect the broncho-
constriction induced by intravenous injection of U-46619,
a TXA2 mimetic, at 10 mg/kg (po) in the guinea pig
model14 (data not shown). Thus the PGD2 receptor
mediated component may have a role in the antigen-
induced increase in specific airway resistance.2c We also
evaluated the effect of compound 19 on antigen-induced
eosinophil infiltration in allergic rhinitis and asthma
models. Compound 19 effectively reduced the increase
in eosinophil number in nasal lavage fluid at 5 h after
intranasal antigen challenge in actively sensitized
guinea pigs16 and in bronchoalveolar lavage fluid at 72
h after inhalation of aerosol antigen,17 the percent
inhibition at 10 mg/kg (po) being 80% (p < 0.01) and
43% (p < 0.05), respectively.
We have described here novel PGD2 receptor antago-
nists, containing bicyclo[2.2.1]heptane and 6,6-dimethyl-
bicyclo[3.1.1]heptane ring systems with characteristic
sulfonylamino or carbonylamino groups, which were
originally synthesized in our laboratories. Although
there are numerous reports on the contribution of PGD2
to the pathogenesis of allergic diseases on the basis of
local production of PGD2 after antigen challenge,18 this
study provides experimental evidence suggesting that
the PGD2 receptor antagonist is effective for alleviating
various allergic diseases. This is the first report of
promising drug candidates for diseases caused by excess
production of PGD2.
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thank Ms. Yoko Furue and Ms. Maki Hattori for their
technical support.

Communications to the Editor
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 22 3507
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J M970343G