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 K_i of 0.51 μM against FABP4, K_i of 33.01 μM 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.

Anti-inflammation; Biphenyl scaffold; FABP4 inhibitor; Oral bioavailability; Selectivity; Structure–activity relationship.