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Discovery of Potent and Selective FABP4/5 Inhibitors with an Isoquinolone Scaffold as Potential Therapeutics for Inflammation-Related Diseases

文献类型：期刊论文

作者He, Yulong3; Li, Shunyi1,2; Chen, Yuqi3; Xu, Yiyang1,2; Wang, Yujie3; Chen, Zonglong3; Wang, Heyao1,2; Li, Yingxia3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-10-09
卷号68期号:19页码:20207-20227
ISSN号0022-2623
DOI10.1021/acs.jmedchem.5c01256
通讯作者Chen, Zonglong(zlchen19@fudan.edu.cn) ; Wang, Heyao(hywang@simm.ac.cn) ; Li, Yingxia(liyx417@fudan.edu.cn)
英文摘要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 K i values of 0.41 and 2.53 mu M for FABP4 and FABP5, respectively. Notably, Y18 achieves significantly improved selectivity over FABP3 (K i = 59.72 mu M) 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.
WOS关键词BINDING PROTEIN 4 ; DRUG
资助项目National Natural Science Foundation of China[81973178] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040336] ; State Key Laboratory of Drug Research[SIMM1803KF-05]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001578265600001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/321525]  
专题中国科学院上海药物研究所
通讯作者Chen, Zonglong; Wang, Heyao; Li, Yingxia
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
3.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 He, Yulong,Li, Shunyi,Chen, Yuqi,et al. Discovery of Potent and Selective FABP4/5 Inhibitors with an Isoquinolone Scaffold as Potential Therapeutics for Inflammation-Related Diseases[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(19):20207-20227.
APA He, Yulong.,Li, Shunyi.,Chen, Yuqi.,Xu, Yiyang.,Wang, Yujie.,...&Li, Yingxia.(2025).Discovery of Potent and Selective FABP4/5 Inhibitors with an Isoquinolone Scaffold as Potential Therapeutics for Inflammation-Related Diseases.JOURNAL OF MEDICINAL CHEMISTRY,68(19),20207-20227.
MLA He, Yulong,et al."Discovery of Potent and Selective FABP4/5 Inhibitors with an Isoquinolone Scaffold as Potential Therapeutics for Inflammation-Related Diseases".JOURNAL OF MEDICINAL CHEMISTRY 68.19(2025):20207-20227.

入库方式： OAI收割

来源：上海药物研究所

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