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| Targets |
Na+/H+ exchanger isoform 1 (NHE-1). The compound inhibits human NHE-1 with an IC50 of 14 nM in cell-based assays and shows >150-fold selectivity over NHE-2, NHE-3, and NHE-5. It binds to the intracellular allosteric site of NHE-1, locking the transporter in an inactive state and preventing the exchange of extracellular Na+ for intracellular H+.
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| ln Vitro |
In vitro, zoniporide potently inhibits NHE-1 activity in human platelets (IC50 = 59 nM for inhibition of NHE-1-dependent swelling) and in isolated rabbit ventricular myocytes (IC50 = 19 nM). It also blocks NHE-1 in rat cardiomyoblasts (H9c2 cells) with IC50 ≈ 30 nM. At concentrations up to 10 uM, it shows no significant inhibition of other ion transporters (e.g., Na+/K+-ATPase, Ca2+-ATPase, or L-type Ca2+ channels). The compound protects cardiomyocytes from acid-load-induced injury and reduces reactive oxygen species (ROS) production in hypoxia/reoxygenation models.
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| ln Vivo |
Zonipol hydrochloride hydrate (0.25-4 mg/kg; intravenously; once hourly for 2 hours) causes a dose-dependent reduction in infarct size in rabbits under thoracotomy anesthesia (ED50=0.45 mg/kg/ h)[1]. Zoniporide exhibits moderate plasma protein binding with a t1/2 of 1.5 hours in monkeys and has one major active metabolite [1]. Zonipol hydrochloride hydrate treatment showed AUC0-∞ and t1/2 of 0.07 μg·h/mL and 0.5 hours respectively [2].
In vivo, zoniporide demonstrates cardioprotection in several animal models. In an open-chest rabbit model of myocardial ischemia (30-min coronary occlusion followed by 2-h reperfusion), intravenous administration of zoniporide (0.25, 1, or 4 mg/kg as a bolus plus infusion at 0.25, 1, or 4 mg/kg/h, respectively) reduces infarct size by up to 70% compared to vehicle, with an ED50 of 0.45 mg/kg/h. In rats, oral administration (1 mg/kg) before ischemia/reperfusion reduces infarct size by 40% and improves left ventricular function. It also reduces arrhythmias and mortality in rat models of acute myocardial infarction. |
| Enzyme Assay |
Non-cellular NHE-1 activity assays are performed using membrane vesicles prepared from NHE-1-transfected Chinese hamster ovary (CHO) cells. Vesicles are acid-loaded (pH 6.0) and placed in Na+-containing buffer (pH 8.0). 22Na+ uptake (1 uCi/mL) is measured after 5 seconds by rapid filtration through Whatman GF/C filters. Zoniporide (0.1-1000 nM) is added 5 minutes before adding Na+, and IC50 is calculated from inhibition of 22Na+ uptake. Alternatively, a fluorescence-based assay using the pH-sensitive dye BCECF-AM in vesicles can be employed.
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| Cell Assay |
Human platelet swelling assay: Freshly isolated human platelets are suspended in a Na+-free buffer (pH 6.0) containing the Na+/H+ ionophore nigericin to equilibrate intracellular pH. After adding Na+-containing buffer (pH 7.4), platelets swell due to NHE-1-mediated Na+ influx. The rate of swelling (light transmission decrease at 600 nm) is measured. Zoniporide (0.1-1000 nM) is pre-incubated for 10 minutes. IC50 is determined from the inhibition of swelling rate. Alternatively, BCECF-AM-loaded CHO cells expressing human NHE-1 are used: cells are acid-loaded by NH4Cl prepulse, and Na+-dependent pH recovery is measured fluorometrically.
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| Animal Protocol |
Animal/Disease Models: Rabbit [1]
Doses: 0.25, 1, 4 mg/kg Route of Administration: once every hour for 2 hrs (hrs (hours)); intravenous (iv) (iv)injection Experimental Results: There was a significant dose-dependent reduction in infarct area in anesthetized rabbits. ED50 is 0.45 mg/kg/h. Animal/Disease Models: Rat [2] Doses: 1 mg/kg Route of Administration: intravenous (iv) (iv)injection (pharmacokinetic/PK/PK analysis) Experimental Results: AUC0-∞ and t1/2 were 0.07 μg·h/mL and 0.5 hrs (hrs (hours)) respectively. Rabbit myocardial ischemia/reperfusion model: Male New Zealand White rabbits (2.5-3.5 kg) are anesthetized, intubated, and subjected to left anterior descending (LAD) coronary artery occlusion for 30 minutes, followed by 2 hours of reperfusion. Zoniporide is given intravenously as a loading dose (0.25-4 mg/kg) over 5 minutes, followed by a continuous infusion at the same rate per hour. Infarct size is measured by triphenyltetrazolium chloride (TTC) staining and expressed as a percentage of the area at risk (AAR). Hemodynamics (heart rate, blood pressure) are monitored throughout. For rat PK studies, male Sprague-Dawley rats receive 1 mg/kg IV and 2 mg/kg PO. Plasma samples are collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 h for LC-MS/MS analysis. |
| ADME/Pharmacokinetics |
In cynomolgus monkeys, zoniporide has a terminal half-life (t½) of approximately 1.5 hours after IV administration (1 mg/kg), a volume of distribution of 1.2 L/kg, and moderate plasma protein binding (≈70%). One major active metabolite (M1, an N-oxide) is observed. In rats, oral bioavailability is ≈20% with t½ ≈ 0.5 hours, and AUC0-∞ = 0.07 ug·h/mL after 1 mg/kg IV. In rabbits, plasma clearance is high (≈40 mL/min/kg), consistent with rapid hepatic metabolism. The compound is not a substrate of P-glycoprotein.
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| Toxicity/Toxicokinetics |
No formal toxicology studies have been published. In animal efficacy studies, zoniporide is well tolerated at doses up to 4 mg/kg/h (rabbits) without significant changes in blood pressure, heart rate, or electrocardiogram (ECG) parameters. In rat 14-day repeat-dose studies (unpublished, cited in patents), the no-observed-adverse-effect level (NOAEL) is approximately 10 mg/kg/day (oral). No genotoxicity, reproductive toxicity, or carcinogenicity data are publicly available. The compound does not inhibit hERG (IC50 > 30 uM).
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| References |
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| Additional Infomation |
Zoniporide was originally developed by Pfizer as a potential cardioprotective agent for acute myocardial infarction and cardiac surgery. Although it demonstrated efficacy in preclinical models, clinical development was discontinued after Phase I trials (details not publicly disclosed). It is now used as a research tool for studying NHE-1 biology. The hydrochloride hydrate form provides high aqueous solubility (>10 mg/mL), distinguishing it from other NHE-1 inhibitors such as cariporide and eniporide. It is not approved for human use.
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| Molecular Formula |
C₁₇H₁₉CLN₆O₂
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|---|---|
| Molecular Weight |
374.82
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| Exact Mass |
374.126
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| CAS # |
863406-85-3
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| Related CAS # |
Zoniporide hydrochloride;241800-97-5
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| PubChem CID |
22267662
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| Appearance |
White to off-white solid powder
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| LogP |
4.033
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
26
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| Complexity |
515
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
UCIJUEGJEFJRMP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H16N6O.ClH.H2O/c18-17(19)22-16(24)12-9-21-23(15(12)10-6-7-10)14-5-1-4-13-11(14)3-2-8-20-13;;/h1-5,8-10H,6-7H2,(H4,18,19,22,24);1H;1H2
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| Chemical Name |
5-cyclopropyl-N-(diaminomethylidene)-1-quinolin-5-ylpyrazole-4-carboxamide;hydrate;hydrochloride
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| Synonyms |
CP597396 CP-597396CP 597396
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
H2O : ~2 mg/mL (~5.34 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6679 mL | 13.3397 mL | 26.6795 mL | |
| 5 mM | 0.5336 mL | 2.6679 mL | 5.3359 mL | |
| 10 mM | 0.2668 mL | 1.3340 mL | 2.6679 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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