Exploring the therapeutic potential of deuterated PPARγ agonists for NASH

NASH represents an increasingly prevalent chronic liver disease, and TZDs are investigated as a potential therapeutic strategy. However, the inherent enolic structure of TZDs leads to enantiomeric instability and racemization, often requiring their use as racemic mixtures. We here report the development of a novel TZD-derivative, 9, in which deuterium incorporation at the chiral center was strategically employed to enhance stereoisomeric stability while maintaining the desired pharmacological profile. In vitro, compound 9 displayed robust activity, with an EC₅₀ of 0.32 ± 0.04 μM in HEK293 cells. Pharmacokinetic analysis revealed a C_max of 1693 ± 339 ng/mL and an AUC_0-24h of 8711 ± 871 ng∙h/mL. Furthermore, compound 9 demonstrated superior therapeutic efficacy in a mouse model of NASH. These findings suggest that the compound 9 represents a promising therapeutic candidate for NASH.