Vol. 303, Issue 1, 132-140, October 2002

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

Gary J. Grover, Albert J. D'Alonzo, Raymond B. Darbenzio, Charles S. Parham, Thomas A. Hess and Mohinder S. Bathala

Metabolic and Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Pennington, New Jersey

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 (ED₂₅ = 0.4 mg/kg i.v.) with efficacious plasma concentrations of 0.3 to 1.0 µM, 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.