Discovery of a class of potent gap-junction modifiers as novel antiarrhythmic agents.
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.
Piatnitski Chekler
Eugene L
EL
Wyeth Research, Chemical Sciences, Collegeville, PA 19426, USA. piatnits@gmail.com
Butera
John A
JA
Di
Li
L
Swillo
Robert E
RE
Morgan
Gwen A
GA
Rossman
Eric I
EI
Huselton
Christine
C
Larsen
Bjarne D
BD
Hennan
James K
JK
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
C541429:1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid; D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D011392:Proline