Discovery of (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride (GAP-134)13, an orally active small molecule gap-junction modifier for the treatment of atrial fibrillation

J Med Chem. 2009 Feb 26;52(4):908-11. doi: 10.1021/jm801558d.

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

  • Administration, Oral
  • Animals
  • Anti-Arrhythmia Agents / chemistry*
  • Anti-Arrhythmia Agents / pharmacology
  • Anti-Arrhythmia Agents / therapeutic use
  • Atrial Fibrillation / drug therapy*
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Benzamides / therapeutic use
  • Dipeptides / chemistry
  • Dipeptides / pharmacology
  • Dipeptides / therapeutic use
  • Disease Models, Animal
  • Drug Discovery
  • Gap Junctions / drug effects*
  • Mice
  • Peptide Library
  • Proline / analogs & derivatives*
  • Proline / chemistry
  • Proline / pharmacology
  • Proline / therapeutic use
  • Structure-Activity Relationship

Substances

  • 1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid
  • Anti-Arrhythmia Agents
  • Benzamides
  • Dipeptides
  • Peptide Library
  • Proline