Exploring the therapeutic potential of deuterated PPARγ agonists for NASH

  • Bioorg Med Chem Lett. 2026 Mar:132:130489. doi: 10.1016/j.bmcl.2025.130489.
Xudong Pang  1 ,  Dawei Cui  2 ,  Ruifeng Liu  2 ,  Binhua Lv  3 ,  Cheng-Yun Wang  4
Affiliations
  • 1. Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China; Shanghai Zelgen Pharma-Tech Co., Ltd., Building 3, No. 999, Cailun Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
  • 2. Shanghai Zelgen Pharma-Tech Co., Ltd., Building 3, No. 999, Cailun Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
  • 3. Shanghai Zelgen Pharma-Tech Co., Ltd., Building 3, No. 999, Cailun Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China. Electronic address: [email protected].
  • 4. Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China. Electronic address: [email protected].
PMID: 41319815 DOI: 10.1016/j.bmcl.2025.130489
Abstract

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 Cmax of 1693 ± 339 ng/mL and an AUC0-24h 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.

Keywords
Deuteration; NASH; PPARγ agonist; TZDs.
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