Discovery of FXR/PPAR? dual partial agonist

Farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR)gamma are nuclear receptor 1 superfamily of transcription factors. FXR and PPAR gamma agonists have been individually investigated in clinical trial of anti-diabetic agents in the patients with nonalcoholic fatty liver disease (NAFLD). Regarding recent agonist development, the partial agonists for FXR and PPAR gamma are drawing attention from the standpoint of avoiding overactive responses caused by full agonists. In this article, we report that 18 with a benzimidazole scaffold possesses FXR/PPAR gamma dual partial agonistic activity. In addition, 18 shares the ability to reduce cyclin-dependent kinase 5-mediated phosphorylation of PPAR gamma-Ser273 and the metabolic stability in mouse liver microsome assay. To date, there are no published reports on FXR/PPAR gamma dual partial agonists with biological profiles similar to 18. Thus, the analog would be a feasible candidate as an unprecedented approach to NAFLD associated with type 2 diabetes mellitus.

Automated summary

This study identified a benzimidazole compound 18 with dual partial agonistic activity for FXR and PPAR gamma, which could be a novel candidate for treating NAFLD associated with type 2 diabetes mellitus.