Abstract
A series of lactam sulfonamides has been discovered and optimized as inhibitors of the Kv1.5 potassium ion channel for treatment of atrial fibrillation. In vitro structure-activity relationships from lead structure C to optimized structure 3y are described. Compound 3y was evaluated in a rabbit PD-model and was found to selectively prolong the atrial effective refractory period at submicromolar concentrations.
Keywords:
Atrial fibrillation; IKur; Kv1.5; Lactams; Sulfonamides.
Copyright © 2014 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Dogs
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Half-Life
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Humans
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Kv1.5 Potassium Channel / antagonists & inhibitors*
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Kv1.5 Potassium Channel / metabolism
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Lactams / chemistry*
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Potassium Channel Blockers / chemical synthesis
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Potassium Channel Blockers / chemistry*
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Potassium Channel Blockers / pharmacokinetics
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Pyrrolidinones / chemical synthesis
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Pyrrolidinones / chemistry*
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Pyrrolidinones / pharmacokinetics
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Rabbits
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Rats
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry*
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Sulfonamides / pharmacokinetics
Substances
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Kv1.5 Potassium Channel
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Lactams
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Potassium Channel Blockers
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Pyrrolidinones
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Sulfonamides