Discovery ofPotent and Selective FABP4/5 Inhibitorswith an Isoquinolone Scaffold as Potential Therapeutics for Inflammation-RelatedDiseases

作者：Yulong He, Shunyi Li, Yuqi Chen, Xu Yang, Yujie Wang, Zonglong Chen, Heyao Wang, Yingxia Li · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c01256 · 被引用次数：3 · 研究领域：Peroxisome Proliferator-Activated Receptors、Drug Transport and Resistance Mechanisms、Pharmacological Effects of Natural Compounds

Abstract Fatty acid-binding proteins 4 (FABP4) and 5 (FABP5) have emerged as promising therapeutic targets for inflammation-related diseases. Herein, we report a series of potent and selective FABP4/5 inhibitors featuring an isoquinolone scaffold through scaffold hopping of RO6806051, a dual FABP4/5 inhibitor. Among these, Y18 was identified as the most promising compound, exhibiting potent inhibitory activity with Ki values of 0.41 and 2.53 μM for FABP4 and FABP5, respectively. Notably, Y18 achieves significantly improved selectivity over FABP3 (Ki = 59.72 μM) compared to RO6806051, along with favorable pharmacokinetic properties, including high oral exposure and acceptable bioavailability. Oral administration of Y18 exhibited significant anti-inflammatory effects and attenuated LPS-induced liver injury. As an anti-inflammatory compound, Y18 demonstrates an excellent safety profile with low hERG inhibition and an LD50 value greater than 2000 mg/kg. Taken together, Y18 represents a promising dual FABP4/5 inhibitor candidate for the treatment of inflammation-related diseases.