2. Academic Validation
  3. Tetrahydroisoquinoline-7-carboxamide Derivatives as New Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors

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

  • ACS Med Chem Lett. 2017 Feb 9;8(3):327-332. doi: 10.1021/acsmedchemlett.6b00497.
Zhen Wang 1,  Yali Zhang 2,  Sergio G Bartual 3,  Jinfeng Luo 4,  Tingting Xu 5,  Wenting Du 6,  Qiuju Xun 4,  Zhengchao Tu 4,  Rolf A Brekken 6,  Xiaomei Ren 4,  Alex N Bullock 3,  Guang Liang 2,  Xiaoyun Lu 7,  Ke Ding 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China; State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, China.
  • 2 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University , Wenzhou, People's Republic of China.
  • 3 Structural Genomics Consortium, University of Oxford , Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, U.K.
  • 4 State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.
  • 5 Department of Pulmonary Medicine, The Second Affiliated Hospital, Wenzhou Medical University , Wenzhou, People's Republic of China.
  • 6 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.
  • 7 School of Pharmacy, Jinan University , 601 Huangpu Avenue West, Guangzhou 510632, China.
PMID: 28337325 DOI: 10.1021/acsmedchemlett.6b00497
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.

Keywords

DDR1; acute lung injury (ALI); inflammation; inhibitor; structure−activity relationship (SAR).

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