Novel Isoidide Subunit-Containing Xanthine Oxidase Inhibitors with Potent Hypouricemic Effects.

Gout is one of the most common inflammatory arthritic diseases. Clinically, the need for safer and more effective xanthine oxidase (XO) inhibitors remains unmet. Here, a novel series of isoidide subunit-containing XO inhibitors was developed through structural optimization of febuxostat. Compounds Z23-Z26 and Z28-Z30 exhibited potent in vitro XO inhibitory activity, with IC50 values ranging from 0.5 to 2.2 nM. Subsequent assessments of metabolic stability in liver microsomes from multiple species and hypouricemic effects in animal models led to the identification of Z29 as the most promising compound. It exhibited significant XO inhibition and outstanding serum uric acid (SUA)-lowering efficacy in both mouse and rat acute hyperuricemia models. Furthermore, Z29 showed no toxicity to vascular cells in vitro and demonstrated a favorable safety profile in in vivo evaluations of acute toxicity and cardiotoxicity. These findings highlight Z29 as a promising therapeutic candidate for hyperuricemia and gout.