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
  • 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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