title: Discovery of a class of potent gap-junction modifiers as novel antiarrhythmic agents.
abstract: In an effort to discover potent, orally bioavailable compounds for the treatment of atrial fibrillation (AF) and ventricular tachycardia (VT), we developed a class of gap-junction modifiers typified by GAP-134 (1, R(1)=OH, R(2)=NH(2)), a compound currently under clinical evaluation. Selected compounds with the desired in-vitro profile demonstrated positive in vivo results in the mouse CaCl(2) arrhythmia model upon oral administration.
authors.affiliation: Wyeth Research, Chemical Sciences, Collegeville, PA 19426, USA. piatnits@gmail.com
authors.forename: Eugene L
authors.initials: EL
authors.lastname: Piatnitski Chekler
authors.forename: John A
authors.initials: JA
authors.lastname: Butera
authors.forename: Li
authors.initials: L
authors.lastname: Di
authors.forename: Robert E
authors.initials: RE
authors.lastname: Swillo
authors.forename: Gwen A
authors.initials: GA
authors.lastname: Morgan
authors.forename: Eric I
authors.initials: EI
authors.lastname: Rossman
authors.forename: Christine
authors.initials: C
authors.lastname: Huselton
authors.forename: Bjarne D
authors.initials: BD
authors.lastname: Larsen
authors.forename: James K
authors.initials: JK
authors.lastname: Hennan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000188:drug therapy; D001281:Atrial Fibrillation / Q000188:drug therapy; D001549:Benzamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D055808:Drug Discovery; D017629:Gap Junctions / Q000187:drug effects*; D051379:Mice; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D017180:Tachycardia, Ventricular / Q000188:drug therapy
chemical_list: C541429:1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid; D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D011392:Proline