1vdv
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Bovine Milk Xanthine Dehydrogenase Y-700 Bound Form
OverviewOverview
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.
About this StructureAbout this Structure
1VDV is a Single protein structure of sequence from Bos taurus with CA, FES, MTE, MOS, FAD, YSH, GOL and ACY as ligands. Active as Xanthine dehydrogenase, with EC number 1.17.1.4 Full crystallographic information is available from OCA.
ReferenceReference
Y-700 [1-[3-Cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylic acid]: a potent xanthine oxidoreductase inhibitor with hepatic excretion., Fukunari A, Okamoto K, Nishino T, Eger BT, Pai EF, Kamezawa M, Yamada I, Kato N, J Pharmacol Exp Ther. 2004 Nov;311(2):519-28. Epub 2004 Jun 9. PMID:15190124
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