Abstract
Investigations of a biaryl ether scaffold identified tetrahydronaphthalene Raf inhibitors with good in vivo activity; however these compounds had affinity toward the hERG potassium channel. Herein we describe our work to eliminate this hERG activity via alteration of the substituents on the benzoic amide functionality. The resulting compounds have improved selectivity against the hERG channel, good pharmacokinetic properties and potently inhibit the Raf pathway in vivo.
Keywords:
B-Raf; B-Raf inhibitor; hERG.
Copyright © 2016 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Cell Line, Tumor
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
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Ether-A-Go-Go Potassium Channels / metabolism
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Humans
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Inhibitory Concentration 50
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Male
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Mice
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Mutagenesis
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Neoplasms / drug therapy
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Neoplasms / pathology
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Protein Binding
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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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Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins B-raf / metabolism
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Tetrahydronaphthalenes / chemistry*
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Tetrahydronaphthalenes / pharmacokinetics
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Tetrahydronaphthalenes / therapeutic use
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Transplantation, Heterologous
Substances
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Ether-A-Go-Go Potassium Channels
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Protein Kinase Inhibitors
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Tetrahydronaphthalenes
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Proto-Oncogene Proteins B-raf