Crystal Structures of Mammalian Xanthine Oxidoreductase Bound with Various Inhibitors: Allopurinol, Febuxostat, and FYX-051

Crystal structures of mammalian xanthine oxidoreductase bound with various inhibitors: allopurinol, febuxostat, and FYX-051.

Xanthine oxidoreductase (XOR) catalyzes the reaction of hypoxanthine to xanthine and of xanthine to uric acid. Inhibitors of XOR can thus decrease the concentration of uric acid in serum. Crystal structures of XOR bound with various inhibitors reveal that inhibitors can be categorized into three types, i.e. mechanism-based, structure-based, and hybrid types.

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

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 previ...

The potential renoprotection of xanthine oxidase inhibitors: Febuxostat versus allopurinol

Characterization of N-glucuronidation of 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl) pyridine-2-carbonitrile (FYX-051): a new xanthine oxidoreductase inhibitor.

In humans, orally administered 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl) pyridine-2-carbonitrile (FYX-051) is excreted mainly as triazole N(1)- and N(2)-glucuronides in urine. It is important to determine the enzyme(s) that catalyze the metabolism of a new drug to estimate individual differences and/or drug-drug interactions. Therefore, the characterization and mechanism of these glucuronidatio...

Hyperuricemia-Related Diseases and Xanthine Oxidoreductase (XOR) Inhibitors: An Overview

Uric acid is the final oxidation product of purine metabolism in humans. Xanthine oxidoreductase (XOR) catalyzes oxidative hydroxylation of hypoxanthine to xanthine to uric acid, accompanying the production of reactive oxygen species (ROS). Uric acid usually forms ions and salts known as urates and acid urates in serum. Clinically, overproduction or under-excretion of uric acid results in the e...