Inhibitors of Xanthine Oxidase: Scaffold Diversity and Structure‐Based Drug Design

Xanthine oxidase (XO) is the enzyme responsible for the catabolism of purines and their conversion into uric acid. XO is thus the target for the treatment of hyperuricemia and gout. For more than 50 years the only XO inhibitor drug 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 such as 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 structures and activities 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 XO active site residues for the most important molecules. The challenges ahead for the discovery of new inhibitors of XO with novel chemical structures are discussed. A disease not only of the rich: The worldwide incidence of gout has surged in recent years. High levels of uric acid in the blood are associated not only with gout, but also with diabetes, hypertension, and other cardiovascular diseases. Inhibition of xanthine oxidase (XO), responsible for the production of uric acid, has recently seen a resurgence in attention. After 50 years of allopurinol being the sole treatment for hyperuricemia, two new XO‐inhibiting drugs have entered the market in recent years. This review discusses the molecular structure and activity of the multiple classes of XO inhibitors that have been developed since the discovery of allopurinol. [Image: A swollen and inflamed foot: gout is represented by an attacking demon. Colored soft‐ground etching by James Gillray, 1799. Wellcome Collection, Creative Commons Attribution (CC‐BY 4.0): https://creativecommons.org/licenses/by/4.0.]