非布索坦
黄嘌呤氧化酶
化学
别嘌呤醇
黄嘌呤
嘌呤
黄嘌呤氧化酶抑制剂
尿酸
生物化学
嘌呤核苷磷酸化酶
黄嘌呤脱氢酶
次黄嘌呤
磷酸核糖转移酶
痛风
酶
药理学
嘌呤代谢
高尿酸血症
医学
次黄嘌呤鸟嘌呤磷酸核糖转移酶
内科学
突变体
基因
作者
Yasuhiro Takano,Kumiko Hase-Aoki,Hideki Horiuchi,Lin Zhao,Yoshinori Kasahara,Shirô Kondô,Michael A. Becker
出处
期刊:Life Sciences
[Elsevier]
日期:2005-03-01
卷期号:76 (16): 1835-1847
被引量:285
标识
DOI:10.1016/j.lfs.2004.10.031
摘要
The purine analogue, allopurinol, has been in clinical use for more than 30 years as an inhibitor of xanthine oxidase (XO) in the treatment of hyperuricemia and gout. As consequences of structural similarities to purine compounds, however, allopurinol, its major active product, oxypurinol, and their respective metabolites inhibit other enzymes involved in purine and pyrimidine metabolism. Febuxostat (TEI-6720, TMX-67) is a potent, non-purine inhibitor of XO, currently under clinical evaluation for the treatment of hyperuricemia and gout. In this study, we investigated the effects of febuxostat on several enzymes in purine and pyrimidine metabolism and characterized the mechanism of febuxostat inhibition of XO activity. Febuxostat displayed potent mixed-type inhibition of the activity of purified bovine milk XO, with Ki and Ki′ values of 0.6 and 3.1 nM respectively, indicating inhibition of both the oxidized and reduced forms of XO. In contrast, at concentrations up to 100 μM, febuxostat had no significant effects on the activities of the following enzymes of purine and pyrimidine metabolism: guanine deaminase, hypoxanthine-guanine phosphoribosyltransferase, purine nucleoside phosphorylase, orotate phosphoribosyltransferase and orotidine-5′-monophosphate decarboxylase. These results demonstrate that febuxostat is a potent non-purine, selective inhibitor of XO, and could be useful for the treatment of hyperuricemia and gout.
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