CARDIOSELECTIVE ANTIISCHEMIC ATP-SENSITIVE POTASSIUM CHANNEL OPENERS .4. STRUCTURE-ACTIVITY STUDIES ON BENZOPYRANYLCYANOGUANIDINES - REPLACEMENT OF THE BENZOPYRAN PORTION

The results of our efforts aimed at the replacement of the benzopyran ring of the lead cardiac selective antiischemic ATP-sensitive potassiu m channel (K-ATP) Opener (4) are described. Systematic modification of the benzopyran ring of 4 resulted in the discovery of a structurally simpler acyclic analog (8) with slightly lower antiischemic potency th an the lead compound 4. Further structure-activity studies on the acyc lic analog 8 provided the 2-phenoxy-3-pyridylurea analog 18 with impro ved antiischemic potency and selectivity compared to the benzopyran-ba sed compound 4. These data demonstrate that the benzopyran ring of 4 a nd its congeners is not mandatory for antiischemic activity and cardia c selectivity. The results described in this paper also show that, as for the benzopyran class of compounds, the structure-activity relation ships for the antiischemic and vasorelaxant activities of K-ATP opener s are distinct. The mechanism of action of the acyclic analogs (e.g., 18) still appears to involve K-ATP Opening as their cardioprotective e ffects are abolished by pretreatment with the KATP blocker glyburide.