Discovery of 4-cyclopropyl-3-(2-((1-cyclopropyl-1H-pyrazol-4-yl) amino) quinazolin-6-yl)-N-(3-(trifluoromethyl) phenyl) benzamides as potent discoidin domain receptor inhibitors for the treatment of idiopathic pulmonary fibrosis  

作　　者：Qi Wang Bixi Tang Dandan Sun Ying Dong Yinchun Ji Huanyu Shi Liwei Zhou Yueyue Yang Menglan Luo Qian Tan Lin Chen Yue Dong Cong Li Rongrong Xie Yi Zang Jingkang Shen Bing Xiong Jia Li Danqi Chen 

机构地区：[1]Department of Medicinal Chemistry,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [2]Division of Anti-tumor Pharmacology,State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [3]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [4]University of Chinese Academy of Sciences,Beijing 100049,China [5]Center for Supramolecular Chemistry and Catalysis and Department of Chemistry,College of Sciences,Shanghai University,Shanghai 200444,China [6]Department of Pharmacology,School of Pharmacy,Fudan University,Shanghai 201203,China [7]School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing 210023,China [8]Department of Pulmonary and Critical Care Medicine,Shanghai Fifth People’s Hospital,Fudan University,Shanghai 200240,China [9]Department of Chemistry,College of Sciences,Shanghai University,Shanghai 200444,China [10]School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,UCAS,Hangzhou 310024,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第4期1943-1962,共20页药学学报（英文版）

基　　金：This research has been financially supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDA12020323);the National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”of China(Grant No.2018ZX09711002-004-009);the Strategic Priority Research Program of Chinese Academy of Sciences(No.SIMM010203);Institutes for Drug Discovery and Development,Chinese Academy of Sciences(No.CASIMM0120215009);National Natural Science Foundation of China(No.U1703235);Shanghai Science and Technology Development Funds(18431907100,China).

摘　　要：Idiopathic pulmonary fibrosis(IPF)is a chronic fatal lung disease with a median survival time of 3–5 years.Inaccurate diagnosis,limited clinical therapy and high mortality together indicate that the development of effective therapeutics for IPF is an urgent need.In recent years,it was reported that DDRs are potential targets in anti-fibrosis treatment.Based on previous work we carried out further structure modifications and led to a more selective inhibitor 47 by averting some fibrosis-unrelated kinases,such as RET,AXL and ALK.Extensive profiling of compound 47 has demonstrated that it has potent DDR1/2 inhibitory activities,low toxicity,good pharmacokinetic properties and reliable in vivo anti-fibrosis efficacy.Therefore,we confirmed that discoidin domain receptors are promising drug targets for IPF,and compound 47 would be a promising candidate for further drug development.

关 键 词：Idiopathic pulmonary fibrosis Discoidin domain receptor Kinase Inhibitor Docking 

分 类 号：R914[医药卫生—药物化学]