Synthesis and structure-activity relationships of phenoxypyridine derivatives as novel inhibitors of the sodium-calcium exchanger
A series of 2-phenoxypyridine derivatives were prepared and evaluated for their inhibitory activity against the reverse and forward modes of the sodium-calcium exchanger (NCX). The structure-activity relationships of these compounds on the inhibitory activity for the sodium-calcium exchanger are discussed. The sodium-calcium exchanger (NCX) is known as the transporter that controls the concentration of Ca2+ in cardiac myocytes. In the setting of heart failure and myocardial ischemia-reperfusion, NCX underlies an arrhythmogenic transient inward current responsible for delayed after-depolarizations and nonreentrant initiation of ventricular tachycardia. NCX is an attractive target for treatment in heart failure and myocardial ischemia-reperfusion. We have designed and synthesized a series of phenoxypyridine derivatives, based on compound 3. These derivatives have been evaluated for their inhibitory activity against both the reverse and forward mode of NCX in CCL39 cells. We have discovered several novel potent NCX inhibitors (39q, 48k), which have a high selectivity for reverse NCX inhibitory activity.
Discovery of an N-(2-aminopyridin-4-ylmethyl)nicotinamide derivative: A potent and orally bioavailable NCX inhibitor
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 Ca 2+ 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 IC 50 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.