FYX-051: a novel and potent hybrid-type inhibitor of xanthine oxidoreductase.

Abstract

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 × 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.

• Authors: Koji Matsumoto, Ken Okamoto, Naoki Ashizawa, Takeshi Nishino
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 336 Issue 1 Pg. 95-103 (Jan 2011) ISSN: 1521-0103 [Electronic] United States
• PMID: 20952484 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nitriles
• Pyridines
• FYX-051
• Xanthine Dehydrogenase

Topics

• Animals
• Binding, Competitive (drug effects)
• Cattle
• Crystallography, X-Ray
• Male
• Nitriles (chemistry, pharmacology)
• Pyridines (chemistry, pharmacology)
• Rats
• Rats, Wistar
• Structure-Activity Relationship
• Xanthine Dehydrogenase (antagonists & inhibitors, isolation & purification, metabolism)