2. Academic Validation
  3. 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

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.
John A Butera 1,  Bjarne Due Larsen,  James K Hennan,  Edward Kerns,  Li Di,  Asaf Alimardanov,  Robert E Swillo,  Gwen A Morgan,  Kun Liu,  Qiang Wang,  Eric I Rossman,  Rayomand Unwalla,  Leonard McDonald,  Christine Huselton,  Jørgen S Petersen
Affiliations

Affiliation

  • 1 Chemical Sciences, Wyeth Research, CN 8000, Princeton, New Jersey 08543, USA. Buteraj@wyeth.com
PMID: 19175320 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.

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