Abstract
Rotigaptide (3) is an antiarrhythmic peptide that improves cardiac conduction by modifying gap-junction communication. Small molecule gap-junction modifiers with improved physical properties were identified from a Zealand Pharma peptide library using pharmaceutical profiling, established SAR around 3, and a putative pharmacophore model for rotigaptide. Activity of the compounds was confirmed in a mouse cardiac conduction block model of arrhythmia. Dipeptide 9f (GAP-134) was identified as a potent, orally active gap-junction modifier for clinical development.
MeSH terms
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Administration, Oral
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Animals
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Anti-Arrhythmia Agents / chemistry*
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Anti-Arrhythmia Agents / pharmacology
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Anti-Arrhythmia Agents / therapeutic use
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Atrial Fibrillation / drug therapy*
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Benzamides / chemistry
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Benzamides / pharmacology*
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Benzamides / therapeutic use
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Dipeptides / chemistry
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Dipeptides / pharmacology
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Dipeptides / therapeutic use
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Disease Models, Animal
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Drug Discovery
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Gap Junctions / drug effects*
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Mice
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Peptide Library
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Proline / analogs & derivatives*
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Proline / chemistry
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Proline / pharmacology
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Proline / therapeutic use
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Structure-Activity Relationship
Substances
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1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid
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Anti-Arrhythmia Agents
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Benzamides
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Dipeptides
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Peptide Library
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Proline