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Research ArticleCELLULAR AND MOLECULAR

Y-700 [1-[3-Cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylic Acid]: A Potent Xanthine Oxidoreductase Inhibitor with Hepatic Excretion

Atsushi Fukunari, Ken Okamoto, Takeshi Nishino, Bryan T. Eger, Emil F. Pai, Miho Kamezawa, Ichimaro Yamada and Norihisa Kato
Journal of Pharmacology and Experimental Therapeutics November 2004, 311 (2) 519-528; DOI: https://doi.org/10.1124/jpet.104.070433
Atsushi Fukunari
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Ken Okamoto
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Takeshi Nishino
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Bryan T. Eger
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Emil F. Pai
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Miho Kamezawa
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Ichimaro Yamada
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Norihisa Kato
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Abstract

Y-700 (1-[3-Cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylic acid) is a newly synthesized inhibitor of xanthine oxidoreductase (XOR). Steady-state kinetics with the bovine milk enzyme indicated a mixed type inhibition with Ki and Ki ′ values of 0.6 and 3.2 nM, respectively. Titration experiments showed that Y-700 bound tightly both to the active sulfo-form and to the inactive desulfo-form of the enzyme with Kd values of 0.9 and 2.8 nM, respectively. X-ray crystallographic analysis of the enzyme-inhibitor complex revealed that Y-700 closely interacts with the channel leading to the molybdenum-pterin active site but does not directly coordinate to the molybdenum ion. In oxonate-treated rats, orally administered Y-700 (1–10 mg/kg) dose dependently lowered plasma urate levels. At a dose of 10 mg/kg, the hypouricemic action of Y-700 was more potent and of longer duration than that of 4-hydroxypyrazolo(3,4-d)pyrimidine, whereas its action was approximately equivalent to that of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid, a nonpurine inhibitor of XOR. In normal rats, orally administered Y-700 (0.3–3 mg/kg) dose dependently reduced the urinary excretion of urate and allantoin, accompanied by an increase in the excretion of hypoxanthine and xanthine. Y-700 (1 mg/kg) was absorbed rapidly by the oral route with high bioavailability (84.1%). Y-700 was hardly excreted via the kidneys but was mainly cleared via the liver. These results suggest that Y-700 will be a promising candidate for the treatment of hyperuricemia and other diseases in which XOR may be involved.

Footnotes

  • This study was supported by Grants-in-Aid 11169231 and 12147208 for Science Research on Priority Areas and Grant-in-Aid 13480212 for Science Research from the Ministry of Education, Science, Sports and Culture of Japan (to T.N.) and by a grant from the Canadian Institutes of Health (to E.F.P.). E.F.P. acknowledges support by the Canada Research Chairs Programme.

  • doi:10.1124/jpet.104.070433.

  • ABBREVIATIONS: XOR, xanthine oxidoreductase; XDH, xanthine dehydrogenase; XO, xanthine oxidase; allopurinol, 4-hydroxypyrazolo(3,4-d)pyrimidine; TEI-6720, 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid; Y-700, 1-[3-cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylic acid; AFR, activity/flavin ratio; HPLC, high-performance liquid chromatography; AUC, area under the curve; BOF-4272, sodium-8-(3-methoxy-4-phenylsulfinylphenyl)pyrazolo[1,5-a]-1,3,5-triazine-4-olate monohydrate.

    • Received April 23, 2004.
    • Accepted June 8, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 311 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 311, Issue 2
1 Nov 2004
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Research ArticleCELLULAR AND MOLECULAR

Y-700 [1-[3-Cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylic Acid]: A Potent Xanthine Oxidoreductase Inhibitor with Hepatic Excretion

Atsushi Fukunari, Ken Okamoto, Takeshi Nishino, Bryan T. Eger, Emil F. Pai, Miho Kamezawa, Ichimaro Yamada and Norihisa Kato
Journal of Pharmacology and Experimental Therapeutics November 1, 2004, 311 (2) 519-528; DOI: https://doi.org/10.1124/jpet.104.070433

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Research ArticleCELLULAR AND MOLECULAR

Y-700 [1-[3-Cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylic Acid]: A Potent Xanthine Oxidoreductase Inhibitor with Hepatic Excretion

Atsushi Fukunari, Ken Okamoto, Takeshi Nishino, Bryan T. Eger, Emil F. Pai, Miho Kamezawa, Ichimaro Yamada and Norihisa Kato
Journal of Pharmacology and Experimental Therapeutics November 1, 2004, 311 (2) 519-528; DOI: https://doi.org/10.1124/jpet.104.070433
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