2. Academic Validation
  3. Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors

Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors

  • J Med Chem. 2016 Jun 23;59(12):5911-6. doi: 10.1021/acs.jmedchem.6b00140.
Zhen Wang 1 2,  Huan Bian 3,  Sergio G Bartual 4,  Wenting Du 5,  Jinfeng Luo 1,  Hu Zhao 3,  Shasha Zhang 1,  Cheng Mo 1 2,  Yang Zhou 1 2,  Yong Xu 1,  Zhengchao Tu 1,  Xiaomei Ren 1,  Xiaoyun Lu 1 6,  Rolf A Brekken 5,  Libo Yao 3,  Alex N Bullock 4,  Jin Su 3,  Ke Ding 1 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.
  • 2 University of the Chinese Academy of Sciences , 19 Yuquan Road, Beijing 100049, China.
  • 3 Department of Biochemistry and Molecular Biology, The Fourth Military Medical University , 17 Changle Western Road, Xi'an, Shaanxi 710032, P. R. China.
  • 4 Structural Genomics Consortium, University of Oxford , Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, U.K.
  • 5 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.
  • 6 School of Pharmacy, Jinan University , 601 Huangpu Avenue West, Guangzhou 510632, China.
PMID: 27219676 DOI: 10.1021/acs.jmedchem.6b00140
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.

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