Synthesis and structure–activity relationships of benzyloxyphenyl derivatives as a novel class of NCX inhibitors: effects on heart failure

A series of benzyloxyphenyl derivatives were prepared, and their inhibitory activities against the reverse and forward modes of the sodium–calcium exchanger (NCX) were evaluated. The structure–activity relationships of these compounds are discussed. 6-{4-[(3-Fluorobenzyl)oxy]phenoxy}- N-(pyridin-4-ylmethyl)nicotinamide was further evaluated for its effects in a heart failure model. In the context of heart failure and myocardial ischemia reperfusion, the activity of the sodium–calcium exchanger can lead to calcium overload, which in turn can lead to contractile dysfunction and arrhythmia. Therefore, NCX is an attractive target for treatment of heart failure and myocardial ischemia reperfusion. We have designed and synthesized a series of benzyloxyphenyl derivatives as potential NCX inhibitors, based on compound 4. These derivatives have been evaluated for their inhibitory activity against both the reverse and forward modes of NCX, and two novel potent NCX inhibitors ( 7i, 10a) were discovered. Compound 7i was evaluated for its efficacy on ouabain-induced tonotropy and arrhythmia in a heart-failure model.