| FYX-051: a novel and potent hybrid-type inhibitor of xanthine oxidoreductase. | |
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MedLine Citation:
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PMID: 20952484 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Koji Matsumoto; Ken Okamoto; Naoki Ashizawa; Takeshi Nishino |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-15 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 336 ISSN: 1521-0103 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-12-16 Completed Date: 2011-01-18 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 95-103 Citation Subset: IM |
Affiliation:
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Department of Biochemistry and Molecular Biology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan. |
| Data Bank Information | |
Bank Name/Acc. No.:
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PDB/1FO4; 3AM9 |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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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* |
| Chemical | |
Reg. No./Substance:
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0/FYX-051; 0/Nitriles; 0/Pyridines; EC 1.17.1.4/Xanthine Dehydrogenase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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