Optimization of potent, selective and orally bioavailable biphenyl scaffold as FABP4 inhibitors for anti-inflammation

Fatty-acid binding protein 4 (FABP4) is an essential driver for the progression of metabolic-related inflammatory diseases including obesity, diabetes, atherosclerosis, and various lipid metabolism-related tumors. However, FABP4 inhibitors are not yet available for clinical use, which may be associated with their poor selectivity of FABP3, unsatisfactory efficacy and physicochemical properties. Herein, we reported a systematic optimization of a class of biphenyl scaffold molecules as potent FABP4 inhibitors. Further in vitro and in vivo pharmacokinetic studies identified a selective and orally bioavailable compound 10g, with Ki of 0.51 mu M against FABP4, Ki of 33.01 mu M against FABP3 and bioavailability F% value of 89.4%. In vivo anti-inflammatory efficacy and multi-organ protection study in LPS-induced inflammatory mice model highlighted the potential of compound 10g as a therapeutic candidate in inflammation-related diseases.

Automated summary

Fatty-acid binding protein 4 (FABP4) is a crucial factor in the progression of metabolic-related inflammatory diseases, but there is a lack of clinically available FABP4 inhibitors due to their poor selectivity, efficacy, and physicochemical properties. This study presents the systematic optimization of biphenyl scaffold molecules as potent FABP4 inhibitors. Compound 10g was identified as a selective and orally bioavailable inhibitor, with promising anti-inflammatory efficacy and multi-organ protection in an inflammatory mouse model.