Design,synthesis, and pharmacological and pharmacokinetic evaluation of 3-phenyl-5-pyridyl-1,2,4-triazole derivatives as xanthine oxidoreductase inhibitors |
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Authors: | Takahiro Sato Naoki Ashizawa Takashi Iwanaga Hiroshi Nakamura Koji Matsumoto Tsutomu Inoue Osamu Nagata |
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Affiliation: | 1. Research Laboratories 1, Fuji Yakuhin Co., Ltd, 3936-2 Sashiougi, Nishi-ku, Saitama-shi, Saitama 331-0047, Japan;2. Research Laboratories 2, Medicinal Chemistry Research Department, Fuji Yakuhin Co., Ltd, 636-1 Iidashinden, Nishi-ku, Saitama-shi, Saitama 331-0068, Japan |
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Abstract: | 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. |
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