Discovery of 3-(3-cyano-4-pyridyl)-5-(4-pyridyl)-1,2,4-triazole, FYX-051-a xanthine oxidoreductase inhibitor for the treatment of hyperuricemia

被引：64

作者：

Sato, Takahiro ^{[1
]}

Ashizawa, Naoki ^{[2
]}

Matsumoto, Koji ^{[2
]}

Iwanaga, Takashi ^{[2
]}

Nakamura, Hiroshi ^{[3
]}

Inoue, Tsutomu ^{[1
]}

Nagata, Osamu ^{[2
]}

机构：

[1] Fuji Yakuhin Co Ltd, Med R&D Div, Res Dept, Res Labs 1,Nishi Ku, Saitama 3310047, Japan

[2] Fuji Yakuhin Co Ltd, Med R&D Div, Res Dept, Res Labs 2,Nishi Ku, Saitama 3310068, Japan

[3] Josai Int Univ, Fac Pharmaceut Sci, Togane, Chiba 2838555, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 21期

关键词：

Gout; Xanthine oxidoreductase inhibitor; XO; Hyperuricemia; Triazole derivatives; CYP3A4; Structure-activity relationships; IDENTIFICATION; DRUG;

D O I：

10.1016/j.bmcl.2009.08.091

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：

Our previous study identified 2-[2-(2-methoxy-ethoxy)-ethoxy]-5-[5-(2-methyl-4-pyridyl)-1H-[1,2,4]-triazol-3-yl]-benzonitrile (2) as a safe and potent xanthine oxidoreductase (XOR) inhibitor for the treatment of hyperuricemia. Here, we synthesized a series of 3,5-dipyridyl-1,2,4-triazole derivatives and, in particular, examined their in vivo activity in lowering the serum uric acid levels in rats. As a result, we identified 3-(3-cyano-4-pyridyl)-5-(4-pyridyl)-1,2,4-triazole (FYX-051, compound 39) to be one of the most potent XOR inhibitors; it exhibited an extremely potent in vivo activity, weak CYP3A4-inhibitory activity and a better pharmacokinetic pro. le than compound 2. Compound 39 is currently being evaluated in a phase 2 clinical trial. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：6225 / 6229

页数：5

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