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
Author(s):
John A. Butera, 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
Journal:
Journal of Medicinal Chemistry
Year:
2009
Volume:
52
Pages
908-911
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.