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

Takahiro Sato, Naoki Ashizawa, Takashi Iwanaga, Hiroshi Nakamura, Koji Matsumoto, Tsutomu Inoue, Osamu Nagata

Research Laboratories 1, Fuji Yakuhin Co, Ltd, Saitama-shi, Saitama, Japan. takahiro@fujiyakuhin.co.jp

Bioorganic & medicinal chemistry letters 2009 Jan 1

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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.

Citation

Takahiro Sato, Naoki Ashizawa, Takashi Iwanaga, Hiroshi Nakamura, Koji Matsumoto, Tsutomu Inoue, Osamu Nagata. Design, synthesis, and pharmacological and pharmacokinetic evaluation of 3-phenyl-5-pyridyl-1,2,4-triazole derivatives as xanthine oxidoreductase inhibitors. Bioorganic & medicinal chemistry letters. 2009 Jan 1;19(1):184-7