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CELLULAR 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

Pharmaceutical Research Unit, Mitsubishi Pharma Corporation, Yokohama, Japan (A.F., M.K., I.Y.); Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan (K.O., T.N.); Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada (B.T.E.); Departments of Biochemistry, Medical Biophysics, and Medical Genetics and Microbiology, University of Toronto and Division of Molecular and Structural Biology, Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Ontario, Canada (E.F.P.); and Department of Bioresource Science and Technology, Hiroshima University, Hiroshima, Japan (N.K.)

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 K_i and K_i ' 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 K_d 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.

Address correspondence to: Atsushi Fukunari, Discovery Technology Laboratory, Pharmaceuticals Research Unit, Mitsubishi Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. E-mail: fukunari.atsushi{at}mb.m-pharma.co.jp

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