优化强效、选择性和口服生物利用的联苯骨架作为 FABP4 抑制剂用于抗炎。
Optimization of potent, selective and orally bioavailable biphenyl scaffold as FABP4 inhibitors for anti-inflammation.
机构信息
School of Pharmacy, Fudan University, Shanghai, 201203, China.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
出版信息
Eur J Med Chem. 2023 May 5;253:115319. doi: 10.1016/j.ejmech.2023.115319. Epub 2023 Apr 5.
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 of 0.51 μM against FABP4, K 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（包括肥胖症、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，FABP4 抑制剂尚未用于临床，这可能与其对 FABP3 的选择性差、疗效和理化性质不理想有关。在此，我们报告了一类联苯骨架分子作为有效 FABP4 抑制剂的系统优化。进一步的体外和体内药代动力学研究鉴定出了一种选择性和口服生物利用的化合物 10g，对 FABP4 的 K i 值为 0.51 μM，对 FABP3 的 K i 值为 33.01 μM，生物利用度 F%值为 89.4%。在 LPS 诱导的炎症性小鼠模型中的体内抗炎功效和多器官保护研究强调了化合物 10g 作为炎症相关疾病治疗候选物的潜力。
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