Abstract
The synthesis and biological evaluation of potent and selective anaplastic lymphoma kinase (ALK) inhibitors from a novel class of 2,4-diaminopyrimidines, incorporating 2,3,4,5-tetrahydro-benzo[d]azepine fragments, is described. An orally bioavailable analogue (18) that displayed antitumor efficacy in ALCL xenograft models in mice was identified and extensively profiled.
Copyright © 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Anaplastic Lymphoma Kinase
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Animals
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Benzazepines / chemistry*
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Benzazepines / pharmacokinetics
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Benzazepines / therapeutic use
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Lymphoma, Large-Cell, Anaplastic / drug therapy*
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Mice
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / therapeutic use
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / metabolism
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Pyrimidines / chemistry*
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Pyrimidines / pharmacokinetics
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Pyrimidines / therapeutic use
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Rats
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Rats, Sprague-Dawley
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Receptor Protein-Tyrosine Kinases
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Xenograft Model Antitumor Assays
Substances
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Benzazepines
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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, mouse
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Alk protein, rat
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Anaplastic Lymphoma Kinase
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Protein-Tyrosine Kinases
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Receptor Protein-Tyrosine Kinases