title: 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.
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.
authors.affiliation: Chemical Sciences, Wyeth Research, CN 8000, Princeton, New Jersey 08543, USA. Buteraj@wyeth.com
authors.forename: John A
authors.initials: JA
authors.lastname: Butera
authors.forename: Bjarne Due
authors.initials: BD
authors.lastname: Larsen
authors.forename: James K
authors.initials: JK
authors.lastname: Hennan
authors.forename: Edward
authors.initials: E
authors.lastname: Kerns
authors.forename: Li
authors.initials: L
authors.lastname: Di
authors.forename: Asaf
authors.initials: A
authors.lastname: Alimardanov
authors.forename: Robert E
authors.initials: RE
authors.lastname: Swillo
authors.forename: Gwen A
authors.initials: GA
authors.lastname: Morgan
authors.forename: Kun
authors.initials: K
authors.lastname: Liu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.forename: Eric I
authors.initials: EI
authors.lastname: Rossman
authors.forename: Rayomand
authors.initials: R
authors.lastname: Unwalla
authors.forename: Leonard
authors.initials: L
authors.lastname: McDonald
authors.forename: Christine
authors.initials: C
authors.lastname: Huselton
authors.forename: Jørgen S
authors.initials: JS
authors.lastname: Petersen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000188:drug therapy*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D055808:Drug Discovery; D017629:Gap Junctions / Q000187:drug effects*; D051379:Mice; D019151:Peptide Library; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: C541429:1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid; D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D004151:Dipeptides; D019151:Peptide Library; D011392:Proline