Synthesis and antiarrhythmic activity of cis-2,6-dimethyl-alpha,alpha-diaryl-1-piperidinebutanols.
A series of alpha,alpha-diaryl-1-piperidinebutanols was evaluated for antiarrhythmic activity in the coronary ligated dog model. Structure-activity relationship studies indicated that the 2,6-dimethylpiperidine group yielded compounds with the best antiarrhythmic profiles in this series. The length of the methylene chain separating the diarylcarbinol and the amino group was not crucial. Substitution of a hydrogen or a number of functional groups for the hydroxyl group had little effect on efficacy or duration but yielded compounds that produced severe tachycardias. Replacement of one of the aryl groups by hydrogen or a pyridinyl or cyclohexyl group had little effect on efficacy but decreased the duration of action. Compound 18 (pirmenol) was ultimately chosen for further studies and is now being investigated in man.
Hoefle
M L
ML
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48015.
Blouin
L T
LT
Fleming
R W
RW
Hastings
S
S
Hinkley
J M
JM
Mertz
T E
TE
Steffe
T J
TJ
Stratton
C S
CS
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis; D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003331:Coronary Vessels / Q000502:physiology; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D007202:Indicators and Reagents; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D001593:Benzyl Compounds; D007202:Indicators and Reagents; D010880:Piperidines; C024318:pirmenol