Key Points
- To identify structurally distinct analogs of the cardioprotective potassium channel opener BMS-180448 with improved selectivity for ischemic myocardium over vascular tissue.
- Synthesized 4-(N-aryl)-substituted benzopyran derivatives, modifying the alkyl ester region and substituting it with an imidazole ring.
- Assessed structure-activity relationships, cardioprotective versus vasorelaxant potencies, glyburide-dependent channel blockade, and rat pharmacokinetic profiles.
- Compound 3 (BMS-191095) demonstrated over 20-fold and 4000-fold greater selectivity for ischemic myocardium compared to BMS-180448 and cromakalim, respectively.
- Cardioprotective activity was mediated via potassium channel opening, as cotreatment with the blocker glyburide completely inhibited its cardioprotective effects.
- In rats, compound 3 exhibited favorable pharmacokinetics with 47% oral bioavailability and a plasma elimination half-life of 3 hours.
Structured PICO
PPopulationPreclinical models (rats mentioned for pharmacokinetic studies)
IInterventionCompound 3 (BMS-191095) and other 4-(N-Aryl)-substituted benzopyran derivatives
CComparatorBMS-180448 (2) and cromakalim (1)
OOutcomeSelectivity for ischemic myocardium (ratio of vasorelaxant to cardioprotective potency)surrogate
Compound 3 (BMS-191095) is a highly selective KATP opener for ischemic myocardium, offering a promising candidate for cardioprotection without significant vasorelaxant effects.