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Optimization of potent, selective and orally bioavailable biphenyl scaffold as FABP4 inhibitors for anti-inflammation

文献类型：期刊论文

作者He, Yulong1; Li, Shunyi2,3; Zhu, Yueyue1; Wang, Yujie1; Chen, Yuqi1; Zhang, Deqiang2,3; Wang, Heyao2,3; Li, Yingxia1
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-05-05
卷号253页码:16
ISSN号0223-5234
关键词Structure-activity relationship FABP4 inhibitor Biphenyl scaffold Selectivity Oral bioavailability Anti-inflammation
DOI10.1016/j.ejmech.2023.115319
通讯作者Wang, Heyao(hywang@simm.ac.cn) ; Li, Yingxia(liyx417@fudan.edu.cn)
英文摘要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 Ki of 0.51 mu M against FABP4, Ki of 33.01 mu M 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.
WOS关键词ACID-BINDING PROTEIN ; INSIGHTS ; OBESITY
资助项目National Natural Science Foundation of China[81973178] ; Personalized Medicines -Molecular Signature -based Drug Discovery and Develop- ment? ; 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
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号WOS:000982215600001
源URL[http://119.78.100.183/handle/2S10ELR8/306469]  
专题中国科学院上海药物研究所
通讯作者Wang, Heyao; Li, Yingxia
作者单位1.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 He, Yulong,Li, Shunyi,Zhu, Yueyue,et al. Optimization of potent, selective and orally bioavailable biphenyl scaffold as FABP4 inhibitors for anti-inflammation[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,253:16.
APA He, Yulong.,Li, Shunyi.,Zhu, Yueyue.,Wang, Yujie.,Chen, Yuqi.,...&Li, Yingxia.(2023).Optimization of potent, selective and orally bioavailable biphenyl scaffold as FABP4 inhibitors for anti-inflammation.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,253,16.
MLA He, Yulong,et al."Optimization of potent, selective and orally bioavailable biphenyl scaffold as FABP4 inhibitors for anti-inflammation".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 253(2023):16.

入库方式： OAI收割

来源：上海药物研究所

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