Abstract
A series of novel 2,4-diaminopyrimidine compounds bearing bicyclic aminobenzazepine were synthesized and evaluated for their anti-ALK activities. The activities of these compounds were confirmed in both enzyme- and cell-based ALK assays. Amongst compounds synthesized, KRCA-0445 showed very promising results in pharmacokinetic study and in vivo efficacy study with H3122 xenograft mouse model.
Keywords:
2,4-Diaminopyrimidine; ALK; Cancer.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anaplastic Lymphoma Kinase
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology*
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Benzazepines / chemistry
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Benzazepines / pharmacokinetics
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Benzazepines / pharmacology*
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Bridged Bicyclo Compounds / chemistry
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Bridged Bicyclo Compounds / pharmacokinetics
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Bridged Bicyclo Compounds / pharmacology*
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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Humans
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Mice
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Molecular Structure
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Neoplasms, Experimental / drug therapy*
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Neoplasms, Experimental / pathology
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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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Pyrimidines / chemistry*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology*
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / metabolism
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Benzazepines
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Bridged Bicyclo Compounds
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Protein Kinase Inhibitors
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Pyrimidines
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2,4-diaminopyrimidine
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ALK protein, human
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Alk protein, mouse
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Anaplastic Lymphoma Kinase
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Receptor Protein-Tyrosine Kinases