Document Detail


FYX-051: a novel and potent hybrid-type inhibitor of xanthine oxidoreductase.
MedLine Citation:
PMID:  20952484     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-10-15
Journal Detail:
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:
Created Date:  2010-12-16     Completed Date:  2011-01-18     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  95-103     Citation Subset:  IM    
Affiliation:
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.:
PDB/1FO4;  3AM9
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MeSH Terms
Descriptor/Qualifier:
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:
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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