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.
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.
Butera
John A
JA
Chemical Sciences, Wyeth Research, CN 8000, Princeton, New Jersey 08543, USA. Buteraj@wyeth.com
Larsen
Bjarne Due
BD
Hennan
James K
JK
Kerns
Edward
E
Di
Li
L
Alimardanov
Asaf
A
Swillo
Robert E
RE
Morgan
Gwen A
GA
Liu
Kun
K
Wang
Qiang
Q
Rossman
Eric I
EI
Unwalla
Rayomand
R
McDonald
Leonard
L
Huselton
Christine
C
Petersen
Jørgen S
JS
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
C541429:1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid; D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D004151:Dipeptides; D019151:Peptide Library; D011392:Proline