title: Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors.
abstract: The structure-based design of 1, 2, 3, 4-tetrahydroisoquinoline derivatives as selective DDR1 inhibitors is reported. One of the representative compounds, 6j, binds to DDR1 with a Kd value of 4.7 nM and suppresses its kinase activity with an IC50 value of 9.4 nM, but it is significantly less potent for a panel of 400 nonmutated kinases. 6j also demonstrated reasonable pharmacokinetic properties and a promising oral therapeutic effect in a bleomycin-induced mouse pulmonary fibrosis model.
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.|University of the Chinese Academy of Sciences , 19 Yuquan Road, Beijing 100049, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, The Fourth Military Medical University , 17 Changle Western Road, Xi'an, Shaanxi 710032, P. R. China.
authors.forename: Huan
authors.initials: H
authors.lastname: Bian
authors.affiliation: Structural Genomics Consortium, University of Oxford , Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Sergio G
authors.initials: SG
authors.lastname: Bartual
authors.affiliation: Division of Surgical Oncology, Department of Surgery and the Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center , Dallas Texas 75390-8593, United States.
authors.forename: Wenting
authors.initials: W
authors.lastname: Du
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Biochemistry and Molecular Biology, The Fourth Military Medical University , 17 Changle Western Road, Xi'an, Shaanxi 710032, P. R. China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.|University of the Chinese Academy of Sciences , 19 Yuquan Road, Beijing 100049, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Mo
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.|University of the Chinese Academy of Sciences , 19 Yuquan Road, Beijing 100049, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Zhengchao
authors.initials: Z
authors.lastname: Tu
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.|School of Pharmacy, Jinan University , 601 Huangpu Avenue West, Guangzhou 510632, China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Lu
authors.affiliation: Division of Surgical Oncology, Department of Surgery and the Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center , Dallas Texas 75390-8593, United States.
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
authors.affiliation: Department of Biochemistry and Molecular Biology, The Fourth Military Medical University , 17 Changle Western Road, Xi'an, Shaanxi 710032, P. R. China.
authors.forename: Libo
authors.initials: L
authors.lastname: Yao
authors.affiliation: Structural Genomics Consortium, University of Oxford , Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Alex N
authors.initials: AN
authors.lastname: Bullock
authors.affiliation: Department of Biochemistry and Molecular Biology, The Fourth Military Medical University , 17 Changle Western Road, Xi'an, Shaanxi 710032, P. R. China.
authors.forename: Jin
authors.initials: J
authors.lastname: Su
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.|School of Pharmacy, Jinan University , 601 Huangpu Avenue West, Guangzhou 510632, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001761:Bleomycin; D000070819:Discoidin Domain Receptor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D007546:Isoquinolines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; C000619662:tetrahydroisoquinoline-7-carboxamide; D001761:Bleomycin; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1