Discovery of a Potent and Orally Bioavailable Xanthine Oxidase/Urate Transporter 1 Dual Inhibitor as a Potential Treatment for Hyperuricemia and Gout

Abstract

The main uric acid-lowering agents in clinical use for hyperuricemia and gout are xanthine oxidase (XO) inhibitors or urate transporter 1 (URAT1) inhibitors. While these therapies can partially control the disease, they have various limitations. The development of XO/URAT1 dual inhibitors offers the potential to enhance therapeutic potency and reduce toxicity compared with single-target inhibitors. Through scaffold hopping from the XO inhibitor febuxostat (<b>2</b>) and the URAT1 inhibitor probenecid (<b>3</b>), followed by structure-activity relationship (SAR) studies, we identified compound <b>27</b> as a potent dual inhibitor of XO and URAT1. Compound <b>27</b> demonstrated significant dual inhibition <i>in vitro</i> (XO IC₅₀ = 35 nM; URAT1 IC₅₀ = 31 nM) and exhibited favorable pharmacology and pharmacokinetic (PK) profiles in multiple species including monkeys. Furthermore, toxicity studies in rats and monkeys revealed general safety profiles, supporting that compound <b>27</b> emerges as a promising novel drug candidate with potent XO/URAT1 dual inhibition for the treatment of gout.