Zoniporide: A Potent and Selective Inhibitor of the Human Sodium-Hydrogen Exchan
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The sodium-hydrogen exchanger isoform-1 (NHE-1) plays an important role in the myocardial response to ischemia-reperfusion; inhibition of this exchanger protects against ischemic injury, including reduction in infarct size. Herein we describe a novel, potent, and highly selective NHE-1 inhibitor, zoniporide (CP-597,396; [1-(quinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine). Zoniporide inhibits human NHE-1 with an IC50 of 14 nM, has >150-fold selectivity vs. other NHE isoforms, and potently inhibits ex vivo NHE-1-dependent swelling of human platelets. This compound is well tolerated inpreclinical animal models, exhibits moderate plasma protein binding, has a t1_2 of 1.5 h in monkeys, and has one major active metabolite. In both in vitro and in vivo rabbit models of myocardial ischemia-reperfusion injury, zoniporide markedly reduced infarct size without adversely affecting hemodynamics or cardiac function. In the isolated heart (Langendorff), zoniporide elicited a concentration-dependent reduction in infarct size (EC50= 0.25 nM). At 50 nM it reduced infarct size by 83%. This compound was 2.5–20-fold more potent than either eniporide or cariporide (EC50s of 0.69 and 5.11 nM, respectively), and reduced infarct size to a greater extent than eniporide. In open chest, anesthetized rabbits, zoniporide also elicited a dose-dependent reduction in infarct size (ED50 = 0.45 mg_kg_h) and inhibited NHE-1-mediated platelet swelling (93% inhibition at 4 mg_kg_h). Furthermore, zoniporide attenuated postischemic cardiac contractile dysfunction in conscious primates, and reduced both the incidence and duration of ischemiareperfusion- induced ventricular fibrillation in rats. Zoniporide represents a novel class of potent and selective human NHE-1 inhibitors with potential utility for providing cardioprotection in a clinical setting., http://www.100md.com