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 potassium 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 than the lead compound 4. Further structure-activity studies on the acyclic analog 8 provided the 2-phenoxy-3-pyridylurea analog 18 with improved antiischemic potency and selectivity compared to the benzopyran-based compound 4. These data demonstrate that the benzopyran ring of 4 and its congeners is not mandatory for antiischemic activity and cardiac selectivity. The results described in this paper also show that, as for the benzopyran class of compounds, the structure-activity relationships for the antiischemic and vasorelaxant activities of K-ATP openers are distinct. The mechanism of action of the acyclic analogs (e.g., 18) still appears to involve K-ATP Opening as their cardioprotective effects are abolished by pretreatment with the KATP blocker glyburide.