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
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.08.025