Cardioselective Antiischemic ATP-Sensitive Potassium Channel Openers. 4. Structure−Activity Studies on Benzopyranylcyanoguanidines: Replacement of the Benzopyran Portion

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Abstract
The results of our efforts aimed at the replacement of the benzopyran ring of the lead cardiac selective antiischemic ATP-sensitive potassium channel (KATP) 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 KATP openers are distinct. The mechanism of action of the acyclic analogs (e.g., 18) still appears to involve KATP opening as their cardioprotective effects are abolished by pretreatment with the KATP blocker glyburide.