CARDIOSELECTIVE ANTIISCHEMIC ATP-SENSITIVE POTASSIUM CHANNEL (K-ATP) OPENERS .5. IDENTIFICATION OF 4-(N-ARYL)-SUBSTITUTED BENZOPYRAN DERIVATIVES WITH HIGH SELECTIVITY

This paper describes our studies aimed at the discovery of structurall y distinct analogs of the cardioprotective K-ATP Opener BMS-180448 (2) with improved selectivity for the ischemic myocardium. The starting c ompound 6, derived from the indole analog 4, showed good cardioprotect ive potency and excellent selectivity compared to 2 and the first-gene ration K-ATP opener cromakalim (1). The structure-activity studies ind icate that increasing the size of the alkyl ester leads to diminished potency as does its replacement with a variety of other groups (nitril e, methyl sulfone). Replacement of the ethyl ester of 6 with an imidaz ole gave the best compound 3 (BMS-191095) of this series which maintai ns the potency and selectivity of its predecessor 6. The results descr ibed in this publication further support that there is no correlation between vasorelaxant and cardioprotective potencies of K-ATP openers. Compound 3 is over 20- and 4000-fold more selective far the ischemic m yocardium than 2 and cromakalim (1), respectively. The selectivity for the ischemic myocardium is achieved by reduction of vasorelaxant pote ncy rather than enhancement in antiischemic potency. As for cromakalim (1) and 2, the cardioprotective effects of compound 3 are inhibited b y cotreatment with the K-ATP blocker glyburide, indicating that the K- ATP Opening is involved in its mechanism of cardioprotection With its good oral bioavailability (47%) and plasma elimination half life (3 h) in rats, compound 3 offers an excellent candidate to investigate the role of residual vasorelaxant potency of 2 toward its cardioprotective activity in vivo.