Approach to dual-acting platelet activating factor (PAF) receptor antagonist/thromboxane synthase inhibitor (TxSI) based on the link of PAF antagonists and TxSIs

Article abstract of DOI:10.1016/S0960-894X(01)00731-4

A series of compounds (22-36) which possess dual-acting PAF antagonist/TxSI have been generated by the approach of linking the known PAF antagonists and TxIs, such as Ridogrel (1).

Full text of DOI:10.1016/S0960-894X(01)00731-4

Bioorganic & Medicinal Chemistry Letters 12 (2002) 341–344
Approach to Dual-Acting Platelet Activating Factor (PAF)
Receptor Antagonist/Thromboxane Synthase Inhibitor (TxSI)
Based on the Link of PAF Antagonists and TxSIs
Masakazu Fujita,* Taketsugu Seki, Haruaki Inada, Kazuhiro Shimizu,
Akane Takahama and Tetsuro Sano
Omiya Research Laboratory, Nikken Chemicals Co., Ltd., Kitabukuro-cho, Saitama-shi, Saitama 330-0835, Japan
Received 19 September 2001; accepted 5 November 2001
Abstract—A series of compounds (22–36) which possess dual-acting PAF antagonist/TxSI have been generated by the approach of
linking the known PAF antagonists and TxSIs, such as Ridogrel (1). # 2002 Elsevier Science Ltd. All rights reserved.
Introduction
eficial than either agent alone in the treatment of these
disorders. To avoid the complications associated with
administration of two separate drugs we have engaged in
a program to synthesize agents that possess both the
above biological activities in the same molecule.
Platelet activating factor (PAF) is a mediator of
inflammation and plays important roles in the pathol-
ogy of ischemia/thrombosis,1 septic shock,2 asthma.3
Thromboxane A2 (TxA2) is a potent vasoconstrictor
and platelet aggregating agent, may make an important
contribution to the pathogenesis of various circulatory
and certain renal disorders.4À7 Therefore, it has been
proposed that novel agents combined PAF antagonist
and TxA2 synthase inhibitor (TxSI) would be more ben-
When our program started, dual-acting PAF antago-
nist/TxSI compounds had not been reported in detail.
In general, the design of dual-acting agents has been
based on structural modification of one of the two
potential component structures, so that known SAR
Figure 1.
*Corresponding author. Tel.:+81-48-641-2334; fax:+81-48-641-5749; e-mail: souyaku@jade.dti.ne.jp
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00731-4

342
M. Fujita et al. / Bioorg. Med. Chem. Lett. 12 (2002) 341–344
features of the other component may be incorporated.
In contrast with them, we have examined the feasibility
of a novel approach to the design of these dual-acting
agents, that is to say, the covalent linking of known
PAF antagonist and TxSI compounds.
antagonist compounds to Ridogrel (1) via covalently
phenyl-containing fragment.
Chemistry
We decided to utilize the potent TxSI, Ridogrel (1)8
as a template. Since potent PAF antagonists, such as
RP-66681 (3),9 YM-461 (4),10 BB-182 (5),11 E-6123 (6)
and its analogue (7)12 possess phenyl groups and cyclo-
hexyl groups, and, on the other hand, the TxSI modified
the phenyl groups of Ridogrel (1) and Isbogrel (2),13
had been reported (Fig. 1). In this paper, we describe
the synthesis and pharmacology of dual-acting PAF
antagonist and TxSI compounds by linking PAF
The synthesis of these hybrid compounds is illustrated
in Schemes 1–3. The substituted bromobenzene (8)
which was reacted with nicotinaldehyde in the presence
of BuLi gave the carbinols, followed by oxidation with
MnO2, led to the ketones (9). Reaction with
.
NH2OH HCl followed by alkylation with ethyl 5-bro-
movalerate afforded the esters (10). Deprotection with
TBAF or TFA yielded the alcohols or amine (11),
respectively. The target compounds (13) were provided
n
n
ꢀ
ꢀ
.
Scheme 1. Reagents and conditions: (a) nicotinaldehyde, BuLi, THF, À78 C; (b) MnO2, CH2Cl2, 50 C, 62–69% (two steps); (c) NH2OH HCl,
EtOH–Py, reflux; (d) Br(CH2)4COOEt, NaH, DMF, 60–95% (two steps); (e) TBAF, THF, quant or TFA, 0 ꢀC, quant; (f) MsCl, TEA, CH2Cl2,
quant; (g) SOCl2, CH2Cl2, 80%-quant; (h) amines, NaH, DMF, 0 ꢀC or K2CO3, 18C6, THF, 80 ꢀC, 6-92%; (i) (1) carboxylic acids, (COCl)2, NaH,
cat. DMF, THF; (2) Py–CH2Cl2, 92%-quant; (j) (1) nicotinonitrile, nBuLi, THF, À78 ꢀC; (2) concd HCl, 55–79%.
n
ꢀ
.
Scheme 2. Reagents and conditions: (a) 3-bromopyridine, BuLi, THF, À78 C, 61%; (b) MnO2, CH2Cl2, reflux, 96%; (c) NH2OH HCl, EtOH–Py,
reflux, quant; (d) Br(CH2)4COOEt, NaH, DMF, 81%; (e) H2, 10% Pd/C, AcOH, MeOH, 93%.
Scheme 3. Reagents and conditions: (a) phthalic anhydride, nBuLi, Et2O, À78 ꢀC, 49%; (b) (1) N-BOC-piperazine, DCC, HOBT, THF; (2) TFA,
0 ꢀC, 62%; (c) N-Boc-2-(3-pyridyl)thiazolidine-4-carboxylic acid, DCC, HOBT, DMF, 57%; (d) NH2OH HCl, EtOH–Py, reflux; (e)
.
Br(CH2)4COOEt, NaH, DMF; (f) TFA, 0 ꢀC, 30% (three steps).

M. Fujita et al. / Bioorg. Med. Chem. Lett. 12 (2002) 341–344
343
Table 1. In vitro PAF antagonist and TxA2 synthase inhibitory activities of compounds 22–37
Compd
R3
R5
Position
E/Z
PAF antagonist
activitya IC50 (mM)
TxA2 synthase inhibitionb
IC50 (mM)
23
24
Et
Et
3
4
2:3
3:4
>1.0
>1.0
0.021
0.021
25
26
Et
Et
3
4
2:3
2:3
0.45
0.55
0.0012
0.0036
27
28
29
Et
Et
H
3
4
3
2:3
1:1
2:3
0.20
0.28
>1.0
0.088
0.072
0.012
22
Et
2
2:3
0.56
>1.0
30
31
Et
Et
3
4
2:3
2:3
0.48
0.61
0.052
0.044
32
33
34
Et
Et
H
3
3
3
10:0
0:10
10:0
0.068
0.068
>1.0
0.0047
0.0058
0.0018
35
36
Et
Et
3
4
2:3
2:3
0.06
0.10
0.065
0.072
37
H
Et
2:3
NTc
0.036
0.029
NT
0.0010
NT
NT
0.024
0.00089
(Æ)-E6123 (6)
UK7450514
Ozagrel
Isbogrel (2)
NT
aInhibition of the PAF-induced platelet aggregation in rabbit platelet rich plasma (PRP). This was performed according to the method of Terashita
et al. with slight modification.15
bInhibition of TxB2 production by incubating prostaglandin H2(PGH2) with human platelet microsomes. This was performed according to the
method of Terashita et al. with slight modification.16
cNT, not tested.

344
M. Fujita et al. / Bioorg. Med. Chem. Lett. 12 (2002) 341–344
by condensation of the amine (11) and the carboxylic
acids, or reaction of the leaving groups-containing
compounds (12) and the amines. In the case of com-
pounds 32 and 33, these were synthesized in con-
siderably lower yield in order to be obtained much more
compounds coupling one amine molecule with two ester
molecules. On the other hand, the ketones (14) having
the hydroxyl or amino groupwere given by treatment
with nicotinonitrile in replacement of nicotinaldehyde in
one-pot. Similar methodology enabled the synthesis of
the target compounds (13) via the ketones (14) in
shorter steps (Scheme 1).
results, the ED50 values for compounds 35 and 36
showed 2.3 and 0.5 mg/kg, respectively. On the other
hand, TxSI activity was assessed by ex vivo inhibition of
serum TxB2 production in the rat.16 As the results, the
ED50 values for compounds 23–28 were in the range
0.24–5.0 mg/kg.
In conclusion, we have shown that it is feasible to
covalently phenyl moiety the PAF antagonists to Rido-
grel, so as to give a novel agent which express potent
dual PAF antagonist/TxSI activity in vitro. Our further
work will be reported elsewhere.18
The 3-amino compound (18) was prepared as shown in
Scheme 2 by reduction of the nitro (17) with H2/10%
Pd/C.
References and Notes
1. Braquet, P.; Paubert-Braquet, M.; Koltai, M.; Bourgain, R.;
Bussolino, F.; Hosford, D. Trends Pharm. Sci. 1989, 10, 23.
2. Sanchez-Crespo, M. Drug News Perspect. 1993, 6, 78.
3. (a) Page, C. P. J. Allergy Clin. Immunol. 1988, 81, 144. (b)
Barnes, P. J. J. Allergy Clin. Immunol. 1988, 81, 152.
4. Hirsh, P. D.; Hillis, L. D.; Campbell, W. B.; Firth, B. G.;
Willerson, J. T. N. Engl. J. Med. 1981, 304, 684.
The 2-substituted target compound (22) was provided as
shown in Scheme 3 by reaction of 3-bromopyridine and
phthalic anhydride in the first step, and alkylation with
ethyl 5-bromovalerate in the final step. All the com-
pounds shown in Table 1 were provided by similar
methodology.17
5. Oates, J.; Fitzgerald, G.; Branch, R.; Jackson, E.; Knapp,
H.; Roberts, L. N. Engl. J. Med. 1988, 319, 689.
6. Fitzgerald, D. J.; Roy, L.; Catella, F.; Fitzgerald, G. A. N.
Engl. J. Med. 1986, 315, 983.
7. Fiddler, G.; Lumley, P. Circulation 1990, 81, 69.
8. Hoet, B.; Falcon, C.; De Rey, S.; Arnout, J.; Deckmyn, H.;
Vermylen, J. Blood 1990, 75, 646.
9. Soler, F.; Floch, A.; Robaut, C.; Lave, D.; Cavero, I. Drugs
Future 1992, 17, 207.
10. Yamada, T.; Saito, M.; Mase, T.; Hara, H.; Nagaoka, H.;
Murase, K.; Tomioka, K. Lipids 1991, 26, 1179.
11. Hodgkin, E. E.; Miller, A.; Whittaker, M. Bioorg. Med.
Chem. Lett. 1992, 2, 597.
12. Miyazawa, S.; Okano, K.; Shimomura, N.; Clark, R. S. J.;
Kawahara, T.; Asano, O.; Yoshimura, H.; Miyamoto, M.;
Sakuma, Y.; Muramoto, K.; Obaishi, H.; Harada, K.; Kajima,
T.; Yamada, K.; Tsunoda, H.; Katayama, S.; Abe, S.; Asa-
kawa, N.; Souda, S.; Horie, T.; Sato, T.; Machida, Y.;
Katayama, K.; Yamatsu, I. Chem. Pharm. Bull. 1991, 39, 3215.
13. Kato, K.; Ohkawa, S.; Terao, S.; Terashita, Z.; Nishi-
kawa, K. J. Med. Chem. 1985, 28, 287.
Results and Discussion
Table 1 summarizes the in vitro activity for a selection
of compounds derived from Ridogrel (1). All com-
pounds except for 32–34 were tested as mixtures of E/Z
isomers. The ratios were obtained from the peak height
of proton in the 3-pyridyl moieties for the isomers.
When compounds with a substituent on the phenyl
groupwere compared with
37, the phenyl analogues
were observed to be weaker TxSIs. Especially, introdu-
cing substituent at the 2-position (22) was considerably
less active, nevertheless PAF antagonist activity was
maintained. Compounds 27, 28, 30, and 31 showed
weaker TxSI activity, while the incorporation of a piper-
azinyl moiety improved PAF antagonist activity. In addi-
tion, the methylene groups for linking the piperazinyl
moiety to the phenyl group were preferable to the carbonyl
groups (27, 28 vs 22, 30). Replacement of the ester moiety
with a carboxyl groupindicated more potent TxSI activ-
ity (29, 34). On the contrary, these compounds were
almost completely PAF antagonistic inactive.
14. Cooper, K.; Fray, M. J.; Parry, M. J.; Richardson, K.;
Steele, J. J. Med. Chem. 1992, 35, 3115.
15. Terashita, Z.; Tsushima, S.; Yoshioka, Y.; Nomura, H.;
Inada, Y.; Nishikawa, K. Life Sci. 1983, 32, 1975.
16. Terashita, Z.; Imura, Y.; Tanabe, M.; Kawazoe, K.; Nish-
ikawa, K.; Kato, K.; Terao, S. Thromb. Res. 1986, 41, 223.
17. For additional data related to this work, see: Fujita, M.;
Seki, T.; Inada, H.; Sano, T. J.P. Patent 060570A1, 1997.
18. Fujita, M.; Seki, T.; Inada, H.; Shimizu, K.; Takahama,
A.; Sano, T.; Bioorg. Med. Chem. Lett., to be submitted for
publication.
Furthermore, representative examples of the dual-acting
compounds were tested in or ex vivo after oral admin-
istration. PAF antagonist activity was assessed in the
mouse, using a PAF-induced death assay.14 As the