Abstract
The search for novel, potent Kv1.5 blockers based on an anthranilic amide scaffold employing a pharmacophore-based virtual screening approach is described. The synthesis and structure-activity relationships (SAR) with respect to inhibition of the Kv1.5 channel are discussed. The most potent compounds display sub-micromolar inhibition of Kv1.5 and no significant effect on the HERG channel. In addition, good oral bioavailability is demonstrated for compound 3i in rats.
MeSH terms
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Administration, Oral
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Amides / chemical synthesis
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Amides / pharmacokinetics*
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Amides / pharmacology
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Animals
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Biological Availability
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Dose-Response Relationship, Drug
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Humans
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Inhibitory Concentration 50
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Kv1.5 Potassium Channel
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Models, Molecular
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Potassium Channel Blockers / chemical synthesis*
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Potassium Channel Blockers / pharmacokinetics
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Potassium Channel Blockers / pharmacology
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Potassium Channels, Voltage-Gated / antagonists & inhibitors*
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Rats
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Structure-Activity Relationship
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ortho-Aminobenzoates / chemical synthesis
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ortho-Aminobenzoates / pharmacokinetics
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ortho-Aminobenzoates / pharmacology
Substances
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Amides
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KCNA5 protein, human
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Kcna5 protein, rat
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Kv1.5 Potassium Channel
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Potassium Channel Blockers
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Potassium Channels, Voltage-Gated
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ortho-Aminobenzoates