Fatty acid binding protein 4 (FABP4) plays a critical role in metabolism and inflammatory processes and therefore is a potential therapeutic target for immunometabolic diseases such as diabetes and atherosclerosis. Herein, we reported the identification of naphthalene-1-sulfonamide derivatives as novel, potent and selective FABP4 inhibitors by applying a structure-based design strategy. The binding affinities of compounds 16dk, 16do and 16du to FABP4, at the molecular level, are equivalent to or even better than that of BMS309403. The X-ray crystallography complemented by the isothermal titration calorimetry studies revealed the binding mode of this series of inhibitors and the pivotal network of ordered water molecules in the binding pocket of FABP4. Moreover, compounds 16dk and 16do showed good metabolic stabilities in liver microsomes. Further extensive in vivo study demonstrated that 16dk and 16do exhibited a dramatic improvement in glucose and lipid metabolism, by decreasing fasting blood glucose and serum lipid levels, enhancing insulin sensitivity, and ameliorating hepatic steatosis in obese diabetic (db/db) mice.

脂肪酸结合蛋白4（FABP4）在代谢和炎症过程中起关键作用，因此是免疫代谢疾病（例如糖尿病和动脉粥样硬化）的潜在治疗靶标。在这里，我们报告了通过应用基于结构的设计策略，将萘-1-磺酰胺衍生物鉴定为新型，有效和选择性的FABP4抑制剂。化合物16dk，16do和16du的结合亲和力在分子水平上，对FABP4的抗性等于或什至优于BMS309403。X射线晶体学等温滴定量热法研究的补充，揭示了这一系列抑制剂的结合模式以及FABP4结合口袋中有序水分子的关键网络。此外，化合物16dk和16do在肝微粒体中表现出良好的代谢稳定性。进一步的广泛体内研究表明，通过降低空腹血糖和血清脂质水平，增强胰岛素敏感性以及减轻肥胖糖尿病患者的肝脂肪变性，dbd和16do可以显着改善葡萄糖和脂质代谢（db / db） 老鼠。