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ChemMedChem. 2019 Feb 10. doi: 10.1002/cmdc.201900034. [Epub ahead of print]

Inhibitors of xanthine oxidase: scaffold diversity and structure-based drug design.

Author information

1
Curtin University, School of Pharmacy and Biomedical Sciences, GPO Box U1987, 6845, Perth, AUSTRALIA.
2
AUSTRALIA.
3
MALAYSIA.

Abstract

Xanthine oxidase (XO) is the enzyme responsible for the catabolism of purines in the body and their conversion to uric acid. XO is thus the target enzyme for the treatment of hyperuricemia and gout. For more than 50 years the only drug inhibitor of XO available on the market was the purine analogue allopurinol. In the last decade there has been a resurgence in the search for new inhibitors of XO as the activity of XO and hyperuricemia have also been associated with a variety of conditions like diabetes, hypertension and other cardiovascular diseases. In recent years the non-purine inhibitor febuxostat was approved in Europe and the USA for the treatment of hyperuricemia. This drug was followed by another XO inhibitor called topiroxostat. This review discusses the molecular structure and activity of the multiple classes of inhibitors that have been developed since the discovery of allopurinol, with a brief review of the molecular interactions between inhibitors and amino acid residues in the active site of XO for the most important molecules. The challenges ahead for the discovery of new inhibitors of XO with novel chemical structures is discussed.

KEYWORDS:

Drug Design; Hyperuricemia; Purines; Xanthine Oxidase; inhibitors

PMID:
30740924
DOI:
10.1002/cmdc.201900034

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