摘要
以罗氏公司报道的FABP4/5双靶标抑制剂RO6806051和FABP4抑制剂XU17为先导化合物,根据RO6806051/FABP5复合物和XU17/FABP4复合物晶体结构,通过骨架融合策略设计并合成了20个以喹啉为母核的结构新颖FABP4/5双靶标小分子抑制剂,其结构经核磁共振氢谱(^(1)H NMR)、核磁共振碳谱(^(13)C NMR)和高分辨质谱(HRMS)确证.采用8-苯胺基萘-8-磺酸(1,8-ANS)底物探针置换法对所合成的目标化合物进行了活性测试,活性结果显示,2-(2-(6-氯-4-(2-氯苯基)喹啉-2-基]苯基)乙酸(11a)对FABP4/5表现出较强的抑制活性,其在25μmol/L浓度下对FABP4抑制率为88%,IC_(50)为4.50μmol/L;对FABP5抑制率为73%,IC_(50)为3.9μmol/L.
Taking the dual FABP 4/5 inhibitor RO6806051 and FABP4 inhibitor XU17 as the lead compounds,twenty new quinoline derivatives as dual FABP4/5 inhibitors were designed and synthesized according to the reported RO6806051/FABP5 crystal complex and XU17/FABP4 crystal complex,then confirmed by^(1)H NMR,^(13)C NMR and high-resolution mass spectra(HRMS).All the target compounds were evaluated for their inhibitory activity against FABP4 and FABP5 via the 8-anilinonaphthalene-1-sulfonic acid(1,8-ANS)displacement assay.The results showed that the target compound 2-(2-(6-chloro4-(2-chlorophenyl)quinolin-2-yl)phenyl)acetic acid(11a)exhibited strong inhibitory activity against FABP4(IC_(50):4.50μmol/L)and FABP5(IC_(50):3.90μmol/L).
作者
高建飞
李瞬依
何玉龙
李英霞
王贺瑶
黄二芳
胡春
Gao Jianfei;Li Shunyi;He Yulong;Li Yingxia;Wang Heyao;Huang Erfang;Hu Chun(Key Laboratory of Structure-Based Drug Design&Discovery,Ministry of Education,Shenyang Pharmaceutical University,Shenyang 110015;Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203;School of Pharmacy,Fudan University,Shanghai 201203)
出处
《有机化学》
SCIE
CAS
CSCD
北大核心
2023年第2期636-645,共10页
Chinese Journal of Organic Chemistry
基金
Project supported by the National Natural Science Foundation of China(No.21342006)
the Program for Innovative Research Team of the Ministry of Education(No.IRT_14R36)。
