CARDIOSELECTIVE ANTIISCHEMIC ATP-SENSITIVE POTASSIUM CHANNEL OPENERS .3. STRUCTURE-ACTIVITY STUDIES ON BENZOPYRANYL CYANOGUANIDINES - MODIFICATION OF THE CYANOGUANIDINE PORTION

Structure-activity relationships for the cyanoguanidine portion of the lead cardiac selective ATP-sensitive potassium channel (k(ATP)) opene r (3) are described. The cyanoguanidine moity appears to be optimal si nce increasing or decreasing the distance between the aniline nitrogen and the pendant aromatic ring attenuates anti-ischemic potency/select ivity. Similarly, unfavorable results are obtained by replacement of t he aniline nitrogen with other linkers (CH2, S, 0). Replacement of the phenyl ring with a methyl group diminishes cardiac selectivity. Const raining the urea moiety into a benzimidazolone or imidazolone ring ret ains anti-ischemic potency with significant improvement in cardiac sel ectivity. As shown by the ratio of vasorelaxant and anti-ischemic pote ncies, the cardiac selectivity in vitro varies over 3 orders of magnit ude. These data are in agreement with previous results indicating that distinct structure-activity relationships exist for the anti-ischemic and vasorelaxant activities. Since the anti-ischemic effects of this series of compounds are abolished by pretreatment with structurally di fferent K-ATP blockers (glyburide, sodium 5-hydroxydecanoate, meclofen amic acid), the mechanism for the anti-ischemic actions of these compo unds still appears to involve the opening of K-ATP.