Bioorganic & Medicinal Chemistry Letters 19 (2009) 184–187
Bioorganic & Medicinal Chemistry Letters
Design, synthesis, and pharmacological and pharmacokinetic evaluation
of 3-phenyl-5-pyridyl-1,2,4-triazole derivatives as xanthine
oxidoreductase inhibitors
b
b
a,
Takahiro Sato a, , Naoki Ashizawa , Takashi Iwanaga , Hiroshi Nakamura , Koji Matsumoto b,
*
Tsutomu Inoue a, Osamu Nagata b
a Research Laboratories 1, Fuji Yakuhin Co., Ltd, 3936-2 Sashiougi, Nishi-ku, Saitama-shi, Saitama 331-0047, Japan
b Research Laboratories 2, Medicinal Chemistry Research Department, Fuji Yakuhin Co., Ltd, 636-1 Iidashinden, Nishi-ku, Saitama-shi, Saitama 331-0068, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In an effort to find a potent xanthine oxidoreductase (XO) inhibitor, we discovered the best compound
2-[2-(2-methoxy-ethoxy)-ethoxy]-5-[5-(2-methyl-pyridin-4-yl)-1H-[1,2,4]triazol-3-yl]-benzonitrile 28.
Here, we describe the following: (1) the design, synthesis, and structure–activity relationship of a series
of 3-phenyl-5-pyridyl-1,2,4-triazole derivatives by in vitro studies of XO inhibitory activity in bovine
milk and in vivo studies of serum uric acid (UA) reductive activity in rats, (2) a drug interaction study
by a cytochrome P450 3A4 (CYP3A4) assay, and (3) a pharmacokinetic (PK) study. Compound 28 exhibits
potent XO inhibitory activity, serum UA-lowering activity in rats, weak CYP3A4 inhibitory activity, and
moderate PK profile.
Received 28 July 2008
Revised 7 October 2008
Accepted 28 October 2008
Available online 5 November 2008
Keywords:
Gout
Xanthine oxidoreductase
XO
Ó 2008 Elsevier Ltd. All rights reserved.
Hyperuricemia
Triazole derivatives
CYP3A4
Structure–activity relationship
Gout is a painful disease that is mainly caused by the deposition
of monosodium urate crystals in joints. Various factors are sug-
gested to contribute to the sustained elevation of the uric acid
(UA) level in blood, termed hyperuricemia. Normally, UA is dis-
solved in blood. As a result of hyperuricemia, insoluble UA forms
microscopic crystals in the capillary vessels of joints. These crystals
cause inflammation and sharp pain, which is termed acute gouty
arthritis or acute gout, and result in a significant degradation in
the quality of life of patients. Moreover, some epidemiologic stud-
ies suggest that hyperuricemia is an independent risk factor for
cardiovascular diseases such as myocardial infarction and cerebral
infarction.1 There are two types of drugs for controlling serum
UA—xanthine oxidoreductase (XO) inhibitors and uricosuric
agents. XO inhibitors block the terminal step in UA biosynthesis.2
The only clinically available XO inhibitor is Allopurinol (1) that
has been widely used in clinical practice because it is commonly
tolerated as compared to uricosuric agents (Fig. 1). However, in
patients with renal insufficiency, the plasma half life of oxipurinol,
which is the major active metabolite of allopurinol, is prolonged.
This is because oxipurinol is mainly removed by renal excretion.
Moreover, as a consequence of its structural similarities to purine
compounds, rare but severe hypersensitivity to Allopurinol (1)
has been reported.3 Thus, we have initiated the development of a
novel safe XO inhibitor with non-purine isosteres that is removed
by nonrenal excretion.
Thus far, we have investigated many compounds reported to
exhibit XO inhibitory activities, such as Febuxostat (2) and Y-700
(3) (Fig. 1). We focused on the structural similarities of these XO
inhibitors and prepared various types of acidic compounds; we
found oxanilide-type compound 4 that exhibited weak XO inhibi-
tory activity4 (Fig. 2). We then considered introducing a heterocy-
clic ring moiety for activity reinforcement. Compound 4 was
modified to 4-pyridyl compound 5 that exhibited strong in vitro
COOH
COOH
S
OH
N
NC
O
N
NC
O
N
N
N
N
N
H
* Corresponding author. Tel.: +81 48 625 0071; fax: +81 48 625 0072.
Present address: Faculty of Pharmaceutical Sciences, Josai International Univer-
sity, 1 Gumyo, Togane-shi, Chiba 283-8555, Japan.
Febuxostat (2)
Y-700 (3)
Allopurinol (1)
Figure 1. Structures of Allopurinol 1, Febuxostat 2, and Y-700 3.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.10.122