Design, synthesis, and pharmacological and pharmacokinetic evaluation of 3-phenyl-5-pyridyl-1,2,4-triazole derivatives as xanthine oxidoreductase inhibitors

被引：40

作者：

Sato, Takahiro ^{[1
]}

Ashizawa, Naoki ^{[2
]}

Iwanaga, Takashi ^{[2
]}

Nakamura, Hiroshi ^{[1
]}

Matsumoto, Koji ^{[2
]}

Inoue, Tsutomu ^{[1
]}

Nagata, Osamu ^{[2
]}

机构：

[1] Fuji Yakuhin Co Ltd, Res Labs 1, Nishi Ku, Saitama 3310047, Japan

[2] Fuji Yakuhin Co Ltd, Med Chem Res Dept, Res Labs 2, Nishi Ku, Saitama 3310068, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 01期

关键词：

Gout; Xanthine oxidoreductase; XO; Hyperuricemia; Triazole derivatives; CYP3A4; Structure-activity relationship; CLINICAL-RELEVANCE; DRUG;

D O I：

10.1016/j.bmcl.2008.10.122

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：184 / 187

页数：4

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