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.