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 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.

• Authors: Atsushi Fukunari, Ken Okamoto, Takeshi Nishino, Bryan T Eger, Emil F Pai, Miho Kamezawa, Ichimaro Yamada, Norihisa Kato
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 311 Issue 2 Pg. 519-28 (Nov 2004) ISSN: 0022-3565 [Print] United States
• PMID: 15190124 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylic acid
• Carbon Radioisotopes
• Enzyme Inhibitors
• Pyrazoles
• Xanthine Dehydrogenase
• Xanthine Oxidase

Topics

• Animals
• Carbon Radioisotopes
• Cattle
• Crystallography, X-Ray
• Enzyme Inhibitors (pharmacology)
• Kinetics
• Male
• Milk (enzymology)
• Protein Conformation
• Pyrazoles (adverse effects, chemistry, pharmacokinetics, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Xanthine Dehydrogenase (antagonists & inhibitors)
• Xanthine Oxidase (antagonists & inhibitors, chemistry)