Abstract
A structure-hopping strategy was applied to discover a series of novel 4-aminoquinoline-3-carboxamide derivatives as potent, reversible BTK inhibitors. Compared to the previously described cinnoline scaffold compounds, the 4-aminoquinoline analogues showed significantly improved drug-like properties, especially in their aqueous solubility. The most potent compound, 25, displayed a stronger inhibitory effect on both BTKWT (IC50 = 5.3 nM) and BTKC481S (IC50 = 39 nM). In a rodent collagen-induced arthritis model, compound 25 efficiently reduced paw swelling without a loss in body weight. On the basis of potency, drug-like properties, stability, and noncovalent mode of inhibition, our representative inhibitors could have a promising profile to be treatments for a wide range of autoimmune diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors*
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Agammaglobulinaemia Tyrosine Kinase / metabolism
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Aminoquinolines / chemistry*
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Aminoquinolines / pharmacokinetics
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Aminoquinolines / pharmacology
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Aminoquinolines / therapeutic use*
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Animals
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Arthritis, Experimental / drug therapy*
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Arthritis, Experimental / metabolism
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Arthritis, Rheumatoid / drug therapy
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Arthritis, Rheumatoid / metabolism
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Dogs
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Drug Design
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Haplorhini
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Humans
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Male
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Mice
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Molecular Docking Simulation
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use*
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Rats
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Rats, Sprague-Dawley
Substances
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Aminoquinolines
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Protein Kinase Inhibitors
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Agammaglobulinaemia Tyrosine Kinase
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4-aminoquinoline