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

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 (2)
and the URAT1 inhibitor probenecid (3), followed by structure–activity
relationship (SAR) studies, we identified compound 27 as a potent dual inhibitor of XO and URAT1. Compound 27 demonstrated significant dual inhibition in vitro (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 27 emerges as a promising novel drug candidate
with potent XO/URAT1 dual inhibition for the treatment of gout.