Synthesis and pharmacological characterization of mitochondrial K channel openers with enhanced mitochondriotropic effects.

Mitochondria play a key role for deciding fate of cells and thus are considered an attractive target for pharmacological interventions focused on containment of myocardial ischemia/reperfusion (I/R) injury. Notably, the activation of mitochondrial potassium (mitoK) channels produces a mild depolarization of mitochondrial membrane, that contributes to reduce the driving force to calcium uptake and prevents the formation of mitochondrial transition membrane pore (MPTP); these events underlie anti-ischemic cardioprotection. However, an ideal mitoK channel opener should possess the fundamental requirement to be delivered at mitochondrial level; therefore, to improve the mitochondrial delivery of a previously characterized spirocyclic benzopyrane F81, new compounds have been developed. The three original triphenylphosphonium (TPP)-derivatives of F81 (1-3), were evaluated for their cardioprotective activity on both isolated cardiac mitochondria and cardiac H9c2 cell line. Compound 1 was further investigated in an in vivo infarct model. This work confirms that the TPP strategy applied to mitoKATP openers could foster mitochondrial delivery and enhance the cardioprotective effects of mitochondrial activators of potassium channels.