Cardioselective Antiischemic ATP-Sensitive Potassium Channel (KA TP) Openers. 6. Effect of Modifications at C6 of Benzopyranyl Cyanoguanidines

The effect on potency and selectivity of modifications at the C6 position of the cardioprotective KATP opener BMS-180448 (2) is described. Structure−activity studies show that a variety of electron-withdrawing groups (ketone, sulfone, sulfonamide, etc.) are tolerated for cardioprotective activity as measured by EC25 values for an increase in time to the onset of contracture in globally ischemic rat hearts. Changes made to the sulfonamido substituent indicate that compounds derived from secondary lipophilic amines are preferred for good cardioprotective potency and selectivity. The diisobutyl analogue 27 (EC25 = 0.04 μM) is the most potent compound of this series. The cardiac selectivity of 27 results from a combination of reduced vasorelaxant potency and enhanced cardioprotective potency relative to the potent vasodilating KATP openers (e.g., cromakalim). The diisobutylsulfonamide analogue 27 is over 4 orders of magnitude more cardiac selective than cromakalim (1). These results support the hypothesis that the cardioprotective and vasorelaxant properties of KATP openers follow distinct structure−activity relationships. The mechanism of action of 27 appears to involve opening of the cardiac KATP as its cardioprotective effects are abolished by the KATP blocker glyburide.