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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Bleomycin
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Discoidin Domain Receptor 1 / antagonists & inhibitors*
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Discoidin Domain Receptor 1 / metabolism
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Drug Design*
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Isoquinolines / administration & dosage
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Isoquinolines / chemistry
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Isoquinolines / pharmacology*
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Mice
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Models, Molecular
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Molecular Structure
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Pulmonary Fibrosis / chemically induced
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Pulmonary Fibrosis / drug therapy*
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Structure-Activity Relationship
Substances
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Isoquinolines
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Protein Kinase Inhibitors
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tetrahydroisoquinoline-7-carboxamide
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Bleomycin
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DDR1 protein, human
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Discoidin Domain Receptor 1