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This paper describes the design, synthesis, and biological evaluation of a novel anti-ischemic compound, (2S,3S,4R)-N-(6-amino-3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-2H-benzopyranyl)-N'-benzyl-N"-cyanoguanidine (33), and the structure-activity relationships leading to the discovery of this compound. Compound 33 significantly reduced the myocardial infarct zone to area at risk (IZ/AAR) in the ischemic myocardium rat model with high cardioselectivity. Since the cardioprotective effect of compound 33 is reversed by ATP-sensitive potassium channel (K(ATP)) blockers, its anti-ischemic effect appears to be at least mediated by K(ATP) opening. In addition, compound 33 shows good protective activity on neuronal cells against oxidative stress, and therefore it is suggested that compound 33 may have therapeutic potential both in cardio- and in neuroprotection.

The cardioprotective and hemodynamic effects of KR-31378, a highly cardioselective ATPsensitive potassium channel activator with minimal hypotensive effect, were evaluated in rats and dogs, and compared with those of BMS-191095 and lemakalim. KR-31378 did not show any significant effect on methoxamine-induced aortic constriction up to doses of 300 µM, whereas BMS 191095 produced a moderately potent relaxant effect (IC 50 : 9.0 µM). In conscious rats, KR-31378 slightly increased blood pressure only at high dose (100 mg/kg, iv), unlike BMS-191095 that dose-dependently decreased blood pressure (ED 20 : 2.03 mg/kg). In anesthetized beagle dogs, KR-31378 was approximately 100-fold less potent than BMS-191095 for most hemodynamic parameters (iv ED 20 for blood pressure lowering: 33.7 and 0.37 mg/ kg, respectively). In anesthetized rats subjected to 45-min coronary occlusion and 90-min reperfusion, KR-31378 (iv) dose-dependently reduced the infarct zone from 58.6% to 42.1%, 36.6%, and 34.3% for 0.1, 0.3, and 1.0 mg/kg, respectively (P < 0.05), the effects being comparable to those of BMS 191095. In anesthetized beagle dogs that underwent 2-h occlusion followed by 4.5-h reperfusion, KR-31378 (2 mg/kg, iv infusion) markedly reduced the infarct zone from 48.7% in controls to 19.1% at a dose of 2 mg/kg (P < 0.05). The reduction in infarct zone afforded by KR-31378 in rats was inhibited by pretreatment with selective ATP-sensitive potassium channel blockers, sodium 5-hydroxydecanoate and glibenclamide. These results indicate that KR-31378 is a potent cardioprotective agent with potentially minimal hypotensive effects. Thus, it could be potentially useful in the prevention and treatment of acute myocardial infarction. Drug Dev.