Y-700 [1-[3-cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylic acid]:: A potent xanthine oxidoreductase inhibitor with hepatic excretion
Y-700 [1-[3-cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylic acid]:: A potent xanthine oxidoreductase inhibitor with hepatic excretion
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DOI：
10.1124/jpet.104.070433
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发表时间：
2004-11-01
影响因子：
3.5
通讯作者：
Kato, N
中科院分区：
文献类型：
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作者：
Fukunari, A;Okamoto, K;Kato, N
Y-700 (1-[3-氰基-4-(2,2-二甲基丙氧基)苯基]-1H-吡唑-4-羧酸)是一种新合成的黄嘌呤氧化还原酶(XOR)抑制剂。牛乳酶的稳态动力学表明混合型抑制，K-i 和 K-i' 值分别为 0.6 和 3.2 nM。滴定实验表明，Y-700 与酶的活性磺基形式和非活性脱硫形式紧密结合，K-d 值分别为 0.9 和 2.8 nM。酶-抑制剂复合物的 X 射线晶体分析表明，Y-700 与通向钼-蝶呤活性位点的通道密切相互作用，但不直接与钼离子配位。在接受oxonate治疗的大鼠中，口服Y-700（1-10 mg/kg）可剂量依赖性地降低血浆尿酸盐水平。在剂量为10 mg/kg时，Y-700的降尿酸作用比4-羟基吡唑并(3,4-d)嘧啶更有效且持续时间更长，而其作用大约相当于非嘌呤2-(3-氰基-4-异丁氧基苯基)-4-甲基-5-噻唑甲酸的作用。 XOR抑制剂。在正常大鼠中，口服Y-700（0.3-3 mg/kg）剂量依赖性地减少尿酸盐和尿囊素的尿排泄，同时次黄嘌呤和黄嘌呤的排泄增加。 Y-700（1 mg/kg）通过口服途径吸收迅速，生物利用度高（84.1%）。 Y-700几乎不通过肾脏排泄，主要通过肝脏清除。这些结果表明，Y-700 将成为治疗高尿酸血症和 XOR 可能涉及的其他疾病的有希望的候选药物。
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.