Discovery of an N-(2-aminopyridin-4-ylmethyl)nicotinamide derivative: a potent and orally bioavailable NCX inhibitor Original Research Article

Ca2+ overload in myocardial cells is responsible for arrhythmia. Sodium–calcium exchanger (NCX) inhibitors are more effective than sodium–hydrogen exchanger (NHE) inhibitors with regard to modulation of Ca2+ overload, because NCX inhibitors can directly inhibit the influx of Ca2+ into cells. NCX is an attractive target for the treatment of heart failure and ischemia-reperfusion. We have designed and synthesized a series of N-(2-aminopyridin-4-ylmethyl)nicotinamide derivatives, based on compound 5. We have discovered a novel NCX inhibitor (23h) with an IC50 value of 0.12 μM against reverse NCX. The inhibitory activities of our NCX inhibitors against cytochrome P450 were also evaluated. The effects on heart failure and the pharmacokinetic profile of compound 23h are discussed.