Design and synthesis of 1-(4-benzoylphenyl)imidazole derivatives as new potent 20-HETE synthase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2004.08.025

Structural modification of the novel 20-HETE synthase inhibitor 1 (IC ₅₀ 310 nM) is described. Introduction of a side chain with a carboxylic acid at the terminal position to 1 resulted in increased ability to inhibit human renal microsomal production of 20-HETE (7c: IC₅₀ 7.9 nM), with good selectivity toward CYP2D6 and cyclooxygenases (COX)-1 and -2.

Full text of DOI:10.1016/j.bmcl.2004.08.025

Bioorganic & Medicinal Chemistry Letters 14 (2004) 5305–5308
Design and synthesis of 1-(4-benzoylphenyl)imidazole derivatives
as new potent 20-HETE synthase inhibitors
Toshio Nakamura,* Takaaki Ishii, Noriyuki Miyata, Kazuo Taniguchi,
Yasumitsu Tomishima, Tomokazu Ueki and Masakazu Sato*
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd, 403, Yoshino-Cho 1-Chome,
Kita-ku, Saitama-Shi, Saitama 331-9530, Japan
Received 29 June 2004; revised 11 August 2004; accepted 11 August 2004
Available online 15 September 2004
Abstract—Structural modification of the novel 20-HETE synthase inhibitor 1 (IC50 310nM) is described. Introduction of a side
chain with a carboxylic acid at the terminal position to 1 resulted in increased ability to inhibit human renal microsomal production
of 20-HETE (7c: IC50 7.9nM), with good selectivity toward CYP2D6 and cyclooxygenases (COX)-1 and -2.
Ó 2004 Elsevier Ltd. All rights reserved.
20-Hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE)
is a major metabolite of arachidonic acid (AA) produced
in the kidney.1 Its biological properties have recently
been extensively studied. The formation of 20-HETE
from AA is catalyzed by cytochrome P450 (CYP) 4A
isozymes (CYP4A1, 4A2, 4A3, and 4A8) in rat kidney2
and cerebral artery,3 and by CYP4A11 and 4F2 in
human liver and kidney.4 20-HETE plays an important
role in the regulation of vascular and tubular functions
in kidneys and the regulation of vascular tone in the
brain.3,5–7 Therefore, 20-HETE is now considered to
be a promising new target for the treatment of renal
and cerebrovascular diseases. Several nonspecific 20-
HETE synthase inhibitors such as 1-aminobenzotriazole
(1-ABT),8 and suicide-type inhibitors such as 17-octad-
evcynoic acid (17-ODYA),9 N-methylsulfonyl-12,12-
dibromododec-11-enamide (DDMS), 12,12-dibromodo-
dec-11-enoic acid (DBDD),10 and sodium 10-undecynyl
sulfate (10-SUYS)11 have been reported, however they
received only limited therapeutic evaluation (Fig. 1).
screening of our in-house chemical library (Fig. 1). AA
is metabolized to 20-HETE by oxidation of the x-
carbon atom with the oxygen atom coordinated to the
heme iron atom of 20-HETE synthases. Accordingly,
compound 1 should inhibit 20-HETE synthase activity
through coordination of its imidazole ring to the
active-site heme iron atom of the enzyme, as with well-
known azole CYP inhibitors. On the other hand, AA
has a characteristic carboxylic acid moiety opposite
the hydrophobic terminal, which is recognized by 20-
HETE synthase. Therefore, to improve the potency
and selectivity of 1, we examined the introduction of a
carboxy moiety with a suitable linkage to the site oppo-
site the imidazole ring of compound 1.
Introduction of a carboxy side chain to the 4- and 6-
positions of 1, which may correspond to the expanded
and folded conformations of AA,16 was accomplished
by Fries rearrangement of the o- and p-cresol 4-fluoro-
benzoate (2 and 8) followed by introduction of an imi-
dazole ring and carboxyalkyl moiety (Schemes 1 and
2). Heating of 2 with powdered aluminum chloride with-
out solvent17 gave the benzophenone derivative 3. Alkyl-
ation of 3 by x-bromoalkanoates 4a–f with potassium
carbonate in dimethylformamide at 100°C gave the cor-
responding esters 5a–f. Subsequent treatment of 5a–f
with imidazole and sodium hydride in dimethylform-
amide at 100°C gave the corresponding imidazole deriva-
tives 6a–f. The ester group of 6a–f was hydrolyzed by
1M sodium hydroxide solution in methanol at room
temperature to give the carboxylic acids or sodium salts
We previously described the evaluation of N-hydroxy-
phenylformamidine derivative HET0016 (Fig. 1) as a
selective 20-HETE synthase inhibitor.12–15 We describe
here an evaluation of phenylimidazole derivative 1,
which was obtained along with HET0016 by random
Keyword: 20-HETE.
*
Corresponding authors. Tel.: +81 48 669 3029; fax: +81 48 652
7254; e-mail: toshio.nakamura@po.rd.taisho.co.jp
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.08.025

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T. Nakamura et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5305–5308
H
N
NH
N
COOH
NH2
17-ODYA
1-ABT
IC50>5,000nM
IC50>5,000nM
Br
Br
CONHSO2Me
Br
COOH
Br
DDMS
DBDD
IC50=2,000nM
IC50=2,000nM
H
N
N
OH
NaO
O
S
O
Me
O
10-SUYS
IC50=7,500~12,700nM
HET0016
IC50=35.2nM
O
X
COOH
X=H: Arachidonic Acid
X=OH: 20-HETE
N
N
1 : IC50=310nM
Figure 1. Structures of reported 20-HETE synthase inhibitors and compound 1. IC50 values are for the production of 20-HETE from AA by rat renal
microsome.
-
Br (CH2)n-COOR
Me
Me
F
Me
AlCl3 2eq.
-
1.2eq.
F
OH
F
O (CH2)n-COOR
4a-f
O
130oC
20min
K2CO3 1.2eq.
DMF
O
O
O
100oC 2h
n=3~9, R=Me or Et
5a-f
36%
2
3
89~96%
Me
Me
imidazole 2eq.
NaH 2.1eq.
1M NaOHaq.
N
N
3eq.
-
-
N
O (CH2)n-COOR
N
O (CH2)n-COOH
DMF
MeOH
100oC 2h
r. t. 16h
O
O
44~69%
6a-f
73~99%
7a-f
Scheme 1.
Me
F
N
4 steps
N
O
O
Me
-
O
O (CH2)n-COOH
8
9a-f
Scheme 2.
7a–f. Corresponding 20-carboxyalkyl derivatives 9a–f
were prepared from p-cresol ester 8 in the same way.
ity 4- to 40-fold (Table 1). However, introduction of the
same moieties at the 20-position (9a–f) resulted in a great
loss of activity (1/8 to less than 1/30). These results sug-
gest that the region around the 20-position of compound
1 is spatially limited in the coordination to 20-HETE
synthase. The length of the carboxyalkoxy moiety of
Introduction of a x-carboxyalkoxy moiety with 3–9
methylene groups to the 40-position of compound 1
(7a–f) enhanced the 20-HETE synthase inhibitory activ-

T. Nakamura et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5305–5308
5307
Table 1. Inhibitory activities of 7a–f and 9a–f toward 20-HETE
synthase
thase, were also well accorded. These results suggest that
AA might be located in the active site of 20-HETE syn-
thase with a expanded conformation rather than a
folded conformation, which is thought to be more stable
in solution.16 Selectivity for drug-metabolizing enzymes
(CYP2D6 was inhibited 50.7% by 7c and 71.1% by 1 at
1lM) was also improved by the introduction of a carb-
oxyalkoxy moiety, and 7c did not inhibit the activities of
cyclooxygenases-1 and -2 (COX-1 and COX-2), even at
higher concentrations (100lM). These results indicate
that 7c is a potent and selective inhibitor of the forma-
tion of 20-HETE from AA.
Me
N
N
4'
O
A
HOOC (CH2)
n
2'
O
No.
n
IC50 (nM)a
7
9
a
b
c
d
e
f
3
4
5
6
7
9
13b
12
>10,000
8384
3290
7.9b
22
2461
4797
44
73b
Acknowledgements
6743
a IC50 value for the production of 20-HETE from AA by human renal
microsome (n = 2).
b Sodium salt.
The authors thank Dr. Eiichi Kunioka evaluating the
inhibitory activities toward COX-1 and COX-2, and
Dr. Atsushi Okada for performing the X-ray analysis.
7a–f was clearly correlated with the activity. A sequen-
tial increase in the number of methylene groups from
3 to 5 gradually enhanced the activity. The optimal com-
pound 7c (n = 5) showed an IC50 value of 7.9nM, which
is about 2-fold more potent than 7a (n = 3). An increase
in the number of methylene groups in 7c was sensitively
associated with the loss of activity. Compound 7d (n = 6,
IC50 = 22nM) was about three times weaker than 7c,
and 7f (n = 9) was about ten times weaker than 7c.
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