Design, synthesis, and pharmacological and pharmacokinetic evaluation of 3-phenyl-5-pyridyl-1,2,4-triazole derivatives as xanthine oxidoreductase inhibitors.
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.
Sato
Takahiro
T
Research Laboratories 1, Fuji Yakuhin Co, Ltd, Saitama-shi, Saitama, Japan. takahiro@fujiyakuhin.co.jp
Ashizawa
Naoki
N
Iwanaga
Takashi
T
Nakamura
Hiroshi
H
Matsumoto
Koji
K
Inoue
Tsutomu
T
Nagata
Osamu
O
D000818:Animals; D002417:Cattle; D065692:Cytochrome P-450 CYP3A Inhibitors; D015195:Drug Design; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000138:chemical synthesis; D009570:Nitriles; D010599:Pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D014527:Uric Acid / Q000097:blood; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors*
D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D009570:Nitriles; D014230:Triazoles; D014527:Uric Acid; C014356:benzonitrile; D014968:Xanthine Dehydrogenase