CARDIOSELECTIVE ANTIISCHEMIC ATP-SENSITIVE POTASSIUM CHANNEL OPENERS .2. STRUCTURE-ACTIVITY STUDIES ON BENZOPYRANYLCYANOGUANIDINES - MODIFICATION OF THE BENZOPYRAN RING

The ATP-sensitive potassium channel (K-ATP) openers are of considerabl e interest as myocardial protecting agents. However, there exists a na rrow window of safety for the use of first-generation compounds as ant iischemic agents due to their powerful peripheral vasodilating effects , which can result in underperfusion of the area already at risk. We h ave recently disclosed the discovery of benzopyranylcyanoguanidine typ e K-ATP openers (BMS-180448) which are more selective for the ischemic myocardium compared to the first-generation compounds. This publicati on deals with structure-activity relationships for the antiischemic ac tivity of the lead compound 8. The presence of an electron-withdrawing group at C6, an sp(3) center at C4, and a gem-dimethyl group at C2 ap pears to be essential for antiischemic activity. Cyanoguanidine can be replaced with a urea moiety. The results reported here support the hy pothesis that distinct structure-activity relationships exist for anti ischemic and vaso:relaxant activities of compounds related to 8 and cr omakalim. The trifluoromethyl analog 10 is 550-fold more selective in vitro for the ischemic myocardium compared to the first-generation age nt cromakalim. The reasons for the selectivity of these compounds for the ischemic myocardium are not clear at the present time. They may be related to the existence of receptor subtypes in smooth muscle and th e myocardium.