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 Ki 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.
Footnotes
This work was supported by the Ministry of Education, Science, Sport, and Culture of Japan [Grants 16205021, 20590317] and the National Project on Protein Structural and Functional Analyses.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.174540.
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ABBREVIATIONS:
- XOR
- xanthine oxidoreductase
- XO
- xanthine oxidase
- XDH
- xanthine dehydrogenase
- FYX-051
- 4-[5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile
- 2-hydroxy-FYX-051
- 4-[5-(2-hydroxypyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile
- trihydroxy-FYX-051
- 4-[5-(2,6-dihydroxypyridin-4-yl)-1H-1,2,4-triazol-3-yl]-6-hydroxypyridine-2-carbonitrile
- allopurinol
- 4-hydroxypyrazolo(3,4-d)pyrimidine
- oxipurinol
- 4,6-dihydroxypyrazolo(3,4-d)pyrimidine
- AFR
- activity-to-flavin ratio
- TEI-6720
- 2-(3-cyano-4-isobutoxy-phenyl)-4-methyl-1,3-thiazole-5 carboxylic acid
- Y-700
- 1-[3-cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylic acid
- HPLC
- high-pressure liquid chromatography
- LC/MS
- liquid chromatography/mass spectrometry.
- Received September 8, 2010.
- Accepted October 14, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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