title: 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.affiliation: Discovery Technology Laboratory, Pharmaceuticals Research Unit, Mitsubishi Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. fukunari.atsushi@mb.m-pharma.co.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fukunari
authors.forename: Ken
authors.initials: K
authors.lastname: Okamoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nishino
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Eger
authors.forename: Emil F
authors.initials: EF
authors.lastname: Pai
authors.forename: Miho
authors.initials: M
authors.lastname: Kamezawa
authors.forename: Ichimaro
authors.initials: I
authors.lastname: Yamada
authors.forename: Norihisa
authors.initials: N
authors.lastname: Kato
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes; D002417:Cattle; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008892:Milk / Q000201:enzymology; D011487:Protein Conformation; D011720:Pyrazoles / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: C433950:1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylic acid; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase