Benzimidazoles and isosteric compounds as potent and selective factor Xa inhibitors.

Article abstract of DOI:10.1016/S0960-894X(02)00056-2

Benzimidazoles and their isosteric compounds as factor Xa inhibitors are discussed.

Full text of DOI:10.1016/S0960-894X(02)00056-2

Bioorganic & Medicinal Chemistry Letters 12 (2002) 919–922
Benzimidazoles and Isosteric Compounds as Potent
and Selective Factor Xa Inhibitors
Wei He,* Barbara Hanney, Michael R. Myers, Stephen Condon, Michael R. Becker,
Alfred P. Spada, Christopher Burns, Karen Brown, Dennis Colussi and Valeria Chu
Department of Chemistry, Aventis Pharmaceuticals, Route 202-206, Bridgewater, NJ 08807, USA
Received 30 November 2001; accepted 14 January 2002
Abstract—Benzimidazoles and their isosteric compounds as factor Xa inhibitors are discussed # 2002 Elsevier Science Ltd. All
rights reserved.
Efforts in searching for small molecular inhibitors of
serine protease factor Xa have greatly intensified in
recent years. Consequently, many novel compounds as
factor Xa inhibitors have been identified.1À7 In a pre-
ceding paper,8 we have disclosed that the exploration of
the benzamidine replacement of a novel series of factor
Xa inhibitors led to the discovery of several non-benza-
midine compounds as potent factor Xa inhibitors. Imi-
dazole analogue 2, derived from the initial lead 1, w as
identified as a potent factor Xa inhibitor with a Ki of 12
nM. In addition, compound 2 is also very selective and
essentially inactive against other serine proteases eval-
uated. Meanwhile, aminoquinazoline analogue 3 was
recently reported by our colleagues to be a very potent
and selective inhibitor with a Ki of 0.8 nM.7,9 In an
ongoing effort to discover novel factor Xa inhibitors, we
have undertaken another approach to examine the
structural diversity of compounds 1 and 3 as well as the
tolerance of replacement/substitution of the chloro-
benzothiophene pharmacophore in compounds 1, 2, and
3. Newadvances in the structure–activity relationships
in the piperazine-2-one series of factor Xa inhibitors is
reported herein.
and physical properties from benzothiophenes and thus
such derivatives will possess quite different PK/PD pro-
files. For example, the cLog (3.18) of the parent benz-
imidazole is more than one log unit lower than that of
the corresponding benzothiophene analogue. Thirdly,
SAR can be established rapidly due to ease of synthesis
to assess the tolerance for structural diversity.
The synthesis of aminoquinazoline analogues such as
inhibitor 8 is exemplified in Scheme 1. A variety of dia-
mines 5 were converted to the corresponding chlor-
omethyl-benzimidazoles
6
with chloroacetic acid
according to published procedures.10 Alkylation of
piperizin-2-one template 7,11 with chloromethyl com-
pound 6 was achieved in the presence of sodium hydride
in DMF to afford inhibitor 8.
The synthesis of benzamidine analogues is outlined in
Scheme 2. Alkylation of commercially available piper-
azine-one
9
with para-cyanobenzylbromide was
straightforward to give compound 10, which was then
deprotected with HBr/AcOH12 to give the correspond-
ing HBr salt 11. Alkylation of this salt with benzimida-
zole 6 produced nitrile 12. Subsequent conversion of the
nitrile to benzamidine 13 was achieved with previously
described Pinner reaction conditions.13
Benzimidazole and its isosteric functional groups were
chosen to replace the benzothiophene group with the
rationale presented hereafter. Conformation restriction
via potential hydrogen bonding through N or NH of
benzimidazoles with factor Xa might improve potency.
Secondly, benzimidazoles have very different chemical
The factor Xa and other serine protease assays were
performed as previously described.14 The results of
benzimidazoles and their isosteric compounds as factor
Xa inhibitors are included in Table 1. Compound 15
was founded to be a potent factor Xa inhibitor with a
Ki of 3 nM, although 3-fold less potent than the
corresponding benzothiophene analogue 3. Replace-
ment of the SO2 linker of inhibitor 15 with a CH2 group
*Corresponding author at present address: Drug Discovery, Johnson &
Johnson Pharmaceutical Research & Development LLC, Welsh &
McKean roads, PO Box 776, Spring House, PA 19477-0776, USA. Tel.:
+1-215-628-5525; fax: +1-215-628-4985; e-mail: whe@prius.jnj.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00056-2

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W. He et al. / Bioorg. Med. Chem. Lett. 12 (2002) 919–922
afforded the corresponding alkylamino analogue 8.
Only 3-fold loss of activity was observed between alkyl-
amine 8 and sulfonamide analogue 15 within the benz-
imidazole series of factor Xa inhibitors, which is much
less dramatic than the corresponding comparison
among the benzothiophene analogues. Furthermore,
both alkylamine 8 and sulfonamide 15 are also very
selective against other serine proteases as shown in
Table 2. Replacement of the chlorine atom with a
methyl group resulted in 10-fold loss of activity (18
vs 8). However, substitution with methoxy, tri-
fluoromethyl or dichloro groups abolished anti-factor
Xa activities for benzimidazoles 19, 20, and 21. Such
results are not surprising in light of the unusual binding
mode of a chlorobenzothiophene analogue with factor
Xa (interaction of the chlorine atom with the aromatic
ring of tyrosine 228 in S1 site) as revealed by protein X-
ray crystallography studies.8,10 Co-crystallization of
benzimidazolyl inhibitors with factor Xa was not suc-
cessful, but it is very likely that benzimidazolyl inhibi-
tors also adopt the similar reverse binding mode to that
of benzothiophene analogues considering the structural
similarity between them and the strong preference for
the chlorine atom. However, these two series of inhibi-
tors do possess subtle differences in terms of SAR. In
addition to the difference of alkylamino versus sulfon-
amide inhibitors discussed above, the fact that even the
non-substituted compound 17 (Cl replaced by H)
showed a weakly inhibitory activity seemed to support
our rationale that conformation constrain and hydro-
gen bonding can improve potency. For comparison,
the corresponding non-substituted benzothiophene
analogue was inactive against factor Xa.
Methylation of benzimidazole 8, to remove the hydro-
gen bond donor potential and to explore simple N-sub-
stitutions, resulted in an inseparable mixture of two
isomers 23, which were 30-fold less potent than the non-
methylated parent compound. Replacement of the
chlorine atom with a bromine atom did not offer any
advantage (22 vs 8). Finally, reduction of the amide
group of piperazin-2-one 8 produced the inactive piper-
Scheme 1. Synthesis of aminoquinazoline analogues of factor Xa inhibitors: (i) HCl/ClCH2CO2H; (ii) K2CO3/DMF.
Scheme 2. Synthesis of benzamidine analogues of factor Xa inhibitors: (i) NaH/DMF/4-NCPhCH2Br; (ii) HBr/AcOH; (iii) K2CO3/DMF/ArCH2Cl;
(iv) HCl/MeOH; NH3/MeOH.

W. He et al. / Bioorg. Med. Chem. Lett. 12 (2002) 919–922
921
Table 1. Factor Xa inhibitory activity
Compd
A
B
M
R
X
Y
Z
Ki (nM)
17 (para)a
H
H
N
N
H
H
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
SO2
SO2
SO2
CH2
CH2
SO2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
O
O
O
O
O
O
H,H
O
O
O
O
O
O
O
O
O
O
O
CH
CH
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
S
S
6-Cl
6-Cl
Cl
Cl
Cl
Cl
Cl
H
CH3
O CF3
CF3
5,6-di-Cl
Br
1
1
10
40
37
CH
CH
H
8
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NMe
O
13 (para)a
14 (meta)b
H
>1200
3
> >1200
1200
120
> >1200
> >1200
> >1200
17
290
1200
> >1200
1200
> >1200
24
390
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
Cl
5-Cl
6-Cl
5-Cl
6-Cl
5-Cl
6-Cl
O
S
S
NH
NH
N
CH
CH
O
O
apara-Benzamidine analogue.
bmeta-Benzamidine analogue.
In summary, we have explored the systematic replace-
ment of a key chlorobenzothiophene group in a novel
series of nanomolar factor Xa inhibitors with benzimi-
dazole and its isosteres. This class of compounds is very
selective against factor Xa over other serine proteases
tested. This class of factors Xa inhibitors can be readily
synthesized and might be useful in the further explora-
tion of SAR. Optimization of these prototype com-
pounds may lead to the discovery of novel anti-
coagulation drugs.
Table 2. Selectivity profiles of factor Xa inhibitors
Compd
Ki (nM)
fXa Thrombin Trypsin APC
Plasmin
t-PA
8
15
28
10
3
24
>4000
>4000
>4000
>2900
>2900
>2900
>18,000
>18,000
>18,000
>7300
>7300
>7300
>8700
>8700
>8700
azinyl compound 16. This underscores the importance
of the piperazin-2-one template to overall activity (con-
formational restriction and hydrogen bonding).
References and Notes
Since the methylated analogues 23 are not very active
against factor Xa, it is not surprising that neither ben-
zoxazoles (24 and 25) nor benzothiazoles (26 and 27) are
good inhibitors of factor Xa. The weak activity or
inactivity of these isosteric compounds of benzimidazole
8 might be due to lack of capability to act as hydrogen
bonding donors. This hypothesis is further supported by
the observation that the 5-chloroindole analogue 28,
having a relatively acidic proton, was only 2-fold less
potent than the corresponding 6-chlorobenzimidazole 8.
The 6-chloroindole isomer 29 was much less active with
a Ki of 390 nM probably due to its less optimal geo-
metry to maintain both hydrogen bonding and chlorine/
tyrosine interactions.
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