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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.

Original publication

DOI

10.1021/acs.jmedchem.6b00140

Type

Journal article

Journal

J Med Chem

Publication Date

23/06/2016

Volume

59

Pages

5911 - 5916

Keywords

Administration, Oral, Animals, Bleomycin, Discoidin Domain Receptor 1, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Design, Isoquinolines, Mice, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors, Pulmonary Fibrosis, Structure-Activity Relationship