Design, synthesis, and biological evaluation of novel highly selective non-carboxylic acid FABP1 inhibitors.

Histologic spectrum studies in patients revealed fatty acid binding proteins 1 (FABP1) as a potential new target for the treatment of metabolic associated fatty liver disease. However, there is no FABP1 inhibitor has been reported except the first-in-class FABP1 inhibitor bearing acid moiety reported by our laboratory. Herein, we firstly report the structure-activity relationship of novel non-carboxylic acid FABP1 inhibitors, which resulted in the identification of the potent and selective FABP1 inhibitor 30. The IC50 value of compound 30 for subtype FABP4 in the same family was greater than 80 µM. Moreover, compound 30 significantly alleviated the hepatic steatosis in DIO mice, which is equivalent to that of clinical drug obeticholic acid. This study might be provided a promising probe for the development of FABP1 inhibitors and thus can help to further elucidate the pharmacology of FABP1.

Design, synthesis, and biological studies of novel sulfonamide derivatives as farnesoid X receptor agonists.

Farnesoid X receptor (FXR) is considered as a promising target for the treatment of NASH. Although many non-steroidal FXR agonists have been reported, the structure types are quite scarce and mainly limited to the isoxazole scaffold derived from GW4064. Therefore, it is crucial to expand the structure types of FXR agonist to explore wider chemical space. In this study, the structure-based scaffold hopping strategy was performed by hybrid FXR agonist 1 and T0901317, which resulted in the discovery of sulfonamide FXR agonist 19. Molecular docking study reasonably explained the SAR in this series, and compound 19 fitted well with the binding pocket in a similar mode to the co-crystal ligand. In addition, compound 19 exhibited considerable selectivity against other nuclear receptors. In NASH model, compound 19 alleviated the typical histological features of fatty liver, including steatosis, lobular inflammation, ballooning, and fibrosis. Moreover, compound 19 exhibited acceptable safety profiles with no acute toxicity to major organ. These results suggested that the novel sulfonamide FXR agonist 19 might be a promising agent for the treatment of NASH.