In vivo characterization of the mitochondrial selective K(ATP) opener (3R)-trans-4-((4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)dimethyl-2H-1-benzopyran-6-carbonitril monohydrochloride (BMS-191095): cardioprotective, hemodynamic, and electrophysiological effects.
Recent studies have shown the importance of mitochondrial ATP-sensitive potassium channels (K(ATP)) in cardioprotection, and studies in vitro have shown that the benzopyran analog (3R)-trans- 4-((4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)dimethyl-2H-1-benzopyran-6-carbonitril monohydrochloride (BMS-191095) is a selective mitochondrial K(ATP) opener with cardioprotective activity. The goal of this study was to show selective cardioprotection for BMS-191095 in vivo without hemodynamic or cardiac electrophysiological effects expected for nonselective K(ATP) openers. BMS-191095 reduced infarct size in anesthetized dogs (90-min ischemia + 5-h reperfusion) in a dose-dependent manner (ED(25) = 0.4 mg/kg i.v.) with efficacious plasma concentrations of 0.3 to 1.0 microM, which were consistent with potency in vitro. None of the doses of BMS-191095 tested caused any effect on peripheral or coronary hemodynamic status. Further studies in dogs showed no effects of BMS-191095 on cardiac conduction or action potential configuration within the cardioprotective dose range. In a programmed electrical stimulation model, BMS-191095 showed no proarrhythmic effects, which is consistent with its lack of effects on cardiac electrophysiological status. BMS-191095 is a potent and efficacious cardioprotectant that is devoid of hemodynamic and cardiac electrophysiological side effects of first generation K(ATP) openers, which open both sarcolemmal and mitochondrial K(ATP). Selective opening or activation of mitochondrial K(ATP) seems to be a potentially effective strategy for developing well tolerated and efficacious K(ATP) openers.
Grover
Gary J
GJ
Metabolic and Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Pennington, New Jersey 08534, USA. groverg@bms.com
D'Alonzo
Albert J
AJ
Darbenzio
Raymond B
RB
Parham
Charles S
CS
Hess
Thomas A
TA
Bathala
Mohinder S
MS
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D001578:Benzopyrans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000502:physiology; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology*; D009203:Myocardial Infarction / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D015221:Potassium Channels
C428117:BMS 191095; D001578:Benzopyrans; D002316:Cardiotonic Agents; D007093:Imidazoles; D008565:Membrane Proteins; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel