Progress toward the development of a safe and effective agent for treating reentrant cardiac arrhythmias: synthesis and evaluation of ibutilide analogues with enhanced metabolic stability and diminished proarrhythmic potential.
A series of ibutilide analogues with fluorine substituents on the heptyl side chain was prepared and evaluated for class III antiarrhythmic activity, metabolic stability, and proarrhythmic potential. It was found that fluorine substituents stabilized the side chain to metabolic oxidation. Many of the compounds also retained the ability to increase the refractoriness of cardiac tissue at both slow and fast pacing rates. The potential for producing polymorphic ventricular tachycardia in the rabbit model was dependent on the chirality of the benzylic carbon. The S-enantiomers generally had less proarrhythmic activity than the corresponding racemates. One compound from this series (45E, trecetilide fumarate) had excellent antiarrhythmic activity and metabolic stability and was devoid of proarrhythmic activity in the rabbit model. It was chosen for further development.
Hester
J B
JB
Department of Structural, Analytical & Medicinal Chemistry, Pharmacia Corporation, Kalamazoo, Michigan 49007, USA. jackson.b.hester@pharmacia.com
Gibson
J K
JK
Buchanan
L V
LV
Cimini
M G
MG
Clark
M A
MA
Emmert
D E
DE
Glavanovich
M A
MA
Imbordino
R J
RJ
LeMay
R J
RJ
McMillan
M W
MW
Perricone
S C
SC
Squires
D M
DM
Walters
R R
RR
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D001282:Atrial Flutter / Q000188:drug therapy; D004285:Dogs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011817:Rabbits; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D017180:Tachycardia, Ventricular / Q000188:drug therapy
D000889:Anti-Arrhythmia Agents; D013449:Sulfonamides; C067192:ibutilide; C117132:trecetilide