Discovery of a Prodrug of Bardoxolone Methyl for the Treatment of Acute Lung Injury.

Bardoxolone methyl, also known as CDDO-Me, has demonstrated protective and therapeutic effects on a variety of lung diseases, especially showing great promise for the treatment of acute lung injury (ALI). However, concerns regarding safety and tissue specificity still remain. Herein, we designed and synthesized an H2O2-sensitive CDDO-Me prodrug 2. Results indicated that prodrug 2 can be activated by H2O2 and exhibited the high drug release rate. In RAW 264.7 cells, prodrug 2 demonstrated lower cytotoxicity compared to CDDO-Me. Moreover, prodrug 2 concentration-dependently inhibited NO production in lipopolysaccharide (LPS)-stimulated cells. In an ALI mouse model, prodrug 2 exhibited therapeutic efficacy comparable to CDDO-Me and significantly attenuated the symptoms of LPS-induced lung injury.