Zoniporide: a potent and selective inhibitor of the human sodium-hydrogen exchanger isoform 1 (NHE-1).

Abstract

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 IC(50) 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 in preclinical animal models, exhibits moderate plasma protein binding, has a t(1/2) 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 (EC(50) = 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 (EC(50)s 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 (ED(50) = 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 ischemia-reperfusion-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.

• Authors: W Ross Tracey, Mary C Allen, Donald E Frazier, Anthony A Fossa, Celeste G Johnson, Ravi B Marala, Delvin R Knight, Angel Guzman-Perez
• Journal: Cardiovascular drug reviews (Cardiovasc Drug Rev) Vol. 21 Issue 1 Pg. 17-32 ( 2003) ISSN: 0897-5957 [Print] United States
• PMID: 12595915 (Publication Type: Journal Article, Review)

Chemical References

• Enzyme Inhibitors
• Guanidines
• Pyrazoles
• Sodium-Hydrogen Exchangers
• growth factor-activatable Na-H exchanger NHE-1
• zoniporide

Topics

• Enzyme Inhibitors (chemistry, pharmacology)
• Guanidines (adverse effects, chemistry, pharmacokinetics, pharmacology, toxicity)
• Humans
• Myocardial Reperfusion Injury (drug therapy, physiopathology)
• Pyrazoles (adverse effects, chemistry, pharmacokinetics, pharmacology, toxicity)
• Sodium-Hydrogen Exchangers (antagonists & inhibitors, chemistry)