Structural highlights
Publication Abstract from PubMedFYX-051, 4-[5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile, 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 Ki value of 5.7x10(-9) M, then after a few minutes it formed a tight complex with XOR via a Mo-oxygen-carbon atom covalent linkage, as previously reported (Okamoto et al., 2004). Thus, FYX-051 is a hybrid-type inhibitor exhibiting both structure-based and mechanism-based inhibition. The FYX-051 XOR complex decomposed with a half-life of 20.4 hours, but the enzyme activity did not fully recover. This was found to be due to XOR-mediated conversion of FYX-051 to 2-hydroxy-FYX-051, as well as formation of di- and trihydroxy-FYX-051 during prolonged incubation for up to 72 hours. A distinct charge-transfer band was observed concomitantly with the formation of 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 clinical treatment of hyperuricemia. FYX-051 : A novel and potent hybrid type inhibitor of xanthine oxidoreductase.,Matsumoto K, Okamoto K, Ashizawa N, Nishino T J Pharmacol Exp Ther. 2010 Oct 15. PMID:20952484[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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