FYX-051: A Novel and Potent Hybrid-Type Inhibitor of Xanthine Oxidoreductase
FYX-051: A Novel and Potent Hybrid-Type Inhibitor of Xanthine Oxidoreductase
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DOI：
10.1124/jpet.110.174540
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发表时间：
2011-01-01
影响因子：
3.5
通讯作者：
Nishino, Takeshi
中科院分区：
文献类型：
--
作者：
Matsumoto, Koji;Okamoto, Ken;Nishino, Takeshi
4-[5-(Pyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile (FYX-051) 是牛乳黄嘌呤氧化还原酶 (XOR) 的有效抑制剂。稳态动力学研究表明，它最初表现为竞争型抑制剂，K-i 值为 5.7 x 10(-9) M，然后几分钟后，它通过 Mo-氧-碳原子共价键与 XOR 形成紧密复合物，如先前报道的那样 (Proc Natl Acad Sci USA 101:7931-7936, 2004)。因此，FYX-051是一种混合型抑制剂，同时表现出基于结构和机制的抑制作用。 FYX-051-XOR复合物分解，半衰期为20.4 h，但酶活性并未完全恢复。发现这是由 XOR 介导的 FYX-051 转化为 4-[5-(2-羟基吡啶-4-基)-1H-1,2,4-三唑-3-基]吡啶-2-甲腈 (2-羟基-FYX-051) 以及形成 6-羟基-4-[5-(2-羟基吡啶-4-基)-1H-1,2, 4-三唑-3-基]吡啶-2-甲腈（二羟基-FYX-051）和4-[5-（2,6-二羟基吡啶-4-基）-1H-1,2,4-三唑-3-基]-6-羟基吡啶-2-甲腈（三羟基-FYX-051）长时间孵育长达72小时。随着三羟基-FYX-051-XOR复合物的形成，观察到明显的电荷转移带。电荷转移络合物的晶体分析表明，XOR 的钼和三羟基-FYX-051 的腈基团之间形成了 Mo-氮-碳键。 FYX-051在氧酸钾诱导的高尿酸血症大鼠模型中表现出强效且持久的降尿酸作用，似乎是临床治疗高尿酸血症的有希望的候选者。
4-[5-(Pyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile (FYX-051) is a potent inhibitor of bovine milk xanthine oxidoreductase (XOR). Steady-state kinetics study showed that it initially behaved as a competitive-type inhibitor with a K-i value of 5.7 x 10(-9) M, then after a few minutes it formed a tight complex with XOR via a Mo-oxygen-carbon atom covalent linkage, as reported previously (Proc Natl Acad Sci USA 101:7931-7936, 2004). Thus, FYX-051 is a hybrid-type inhibitor exhibiting both structure-and mechanism-based inhibition. The FYX-051-XOR complex decomposed with a half-life of 20.4 h, but the enzyme activity did not fully recover. This was found to be caused by XOR-mediated conversion of FYX-051 to 4-[5-(2-hydroxypyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile (2-hydroxy-FYX-051), as well as formation of 6-hydroxy-4-[5-(2-hydroxypyridin-4-yl)-1H-1,2, 4-triazol-3-yl] pyridine-2-carbonitrile (dihydroxy-FYX-051) and 4-[5-(2,6-dihydroxypyridin-4-yl)-1H-1,2,4-triazol-3-yl]-6-hydroxypyridine-2-carbonitrile (trihydroxy-FYX-051) during prolonged incubation for up to 72 h. A distinct charge-transfer band was observed concomitantly with the formation of the trihydroxy-FYX-051-XOR complex. Crystallographic analysis of the charge-transfer complex indicated that a Mo-nitrogen-carbon bond was formed between molybdenum of XOR and the nitrile group of trihydroxy-FYX-051. FYX-051 showed a potent and long-lasting hypouricemic effect in a rat model of potassium oxonate-induced hyperuricemia, and it seems to be a promising candidate for the clinical treatment of hyperuricemia.