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.

脂肪酸结合蛋白 4 (FABP4) 是代谢相关炎症性疾病（包括肥胖、糖尿病、动脉粥样硬化和各种脂质代谢相关肿瘤）进展的重要驱动因素。然而，目前尚无FABP4抑制剂用于临床，这可能与其对FABP3的选择性较差、疗效和理化性质不理想有关。在此，我们报道了一种系统优化的一类联苯支架分子作为有效的 FABP4 抑制剂。进一步的体外和体内药代动力学研究确定了一种选择性和口服生物可利用的化合物10g ，其对 FABP4 的K _{i为 0.51 μM，K i}针对 FABP3 的 33.01 μM 和 89.4% 的生物利用度 F% 值。在LPS 诱导的炎症小鼠模型中进行的体内抗炎功效和多器官保护研究突出了化合物10g作为炎症相关疾病治疗候选物的潜力。