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Tetrahydroisoquinoline-7-carboxamide Derivatives as New Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors

DOI: 10.1021/acsmedchemlett.6b00497 DOI Help

Authors: Zhen Wang (Jinan University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences) , Yali Zhang (Wenzhou Medical University) , Sergio G. Bartual (Structural Genomics Consortium, University of Oxford) , Jinfeng Luo (Jinan University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences) , Tingting Xu (Wenzhou Medical University) , Wenting Du (UT Southwestern Medical Center) , Qiuju Xun (Jinan University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences) , Zheng-chao Tu (Jinan University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences) , Rolf A Brekken (UT Southwestern Medical Center) , Xiaomei Ren (Jinan University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences) , Alex N. Bullock (University of Oxford) , Guang Liang (Wenzhou Medical University) , Xiaoyun Lu (Jinan University) , Ke Ding (Jinan University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters

State: Published (Approved)
Published: February 2017
Diamond Proposal Number(s): 10619

Abstract: Acute lung injury (ALI) is a deadly symptom for serious lung inflammation. Discoidin Domain Receptor 1 (DDR1) is a new potential target for anti-inflammatory drug discovery. A new selective tetrahydroisoquinoline-7-carboxamide based DDR1 inhibitor 7ae was discovered to tightly bind the DDR1 protein and potently inhibit its kinase function with a Kd value of 2.2 nM and an IC50 value of 6.6 nM, respectively. The compound dose-dependently inhibited lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) release in mouse primary peritoneal macrophages (MPMs). In addition, 7ae also exhibited promising in vivo anti-inflammatory effects in a LPS-induced mouse ALI model. To the best of our knowledge, this is the first “proof of concept” investigation on the potential application of a small molecule DDR1 inhibitor to treat ALI.

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography