Received for publication April 26, 2004.
Revised June 7, 2004.
Accepted for publication June 8, 2004.

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

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 K_i and K_i' values of 0.6 nM 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 nM 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 allopurinol, whereas its action was approximately equivalent to that of TEI-6720, a non-purine 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.

Key words: Y-700, enzyme inhibitor, gout, hyperuricemia, xanthine dehydrogenase, xanthine oxidase

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