Abstract
The diastereoselective synthesis and biological activity of piperidine-3,4-diol and piperidine-3-ol-derived pyrrolotriazine inhibitors of anaplastic lymphoma kinase (ALK) are described. Although piperidine-3,4-diol and piperidine-3-ol derivatives showed comparable in vitro ALK activity, the latter subset of inhibitors demonstrated improved physiochemical and pharmacokinetic properties. Furthermore, the stereochemistry of the C3 and C4 centers had a marked impact on the in vivo inhibition of ALK autophosphorylation. Thus, trans-4-aryl-piperidine-3-ols (22) were more potent than the cis diastereomers (20).
Keywords:
ALCL; ALK; Inhibitors; Kinase; NSCLC; Pyrrolotriazine.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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 / therapeutic use*
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Cell Line, Tumor
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Crystallography, X-Ray
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Humans
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Lymphoma, Large-Cell, Anaplastic / drug therapy*
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Lymphoma, Large-Cell, Anaplastic / enzymology
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Mice, SCID
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Models, Molecular
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Piperidines / chemistry
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Piperidines / pharmacokinetics
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Piperidines / therapeutic use
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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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Pyrroles / chemistry*
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Pyrroles / pharmacokinetics
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Pyrroles / therapeutic use*
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Rats, Sprague-Dawley
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / metabolism
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Triazines / chemistry*
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Triazines / pharmacokinetics
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Triazines / therapeutic use*
Substances
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Antineoplastic Agents
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Piperidines
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Protein Kinase Inhibitors
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Pyrroles
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Triazines
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pyrrolotriazine-4-one
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piperidine
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ALK protein, human
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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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Receptor Protein-Tyrosine Kinases