ZONIPORIDE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C17H16N6O
Molecular Weight	320.3485
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC(=N)NC(=O)C1=C(C2CC2)N(N=C1)C3=C4C=CC=NC4=CC=C3

InChI

InChIKey=GDXBRVCQGGKXJY-UHFFFAOYSA-N

InChI=1S/C17H16N6O/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)

HIDE SMILES / InChI

Molecular Formula	C17H16N6O
Molecular Weight	320.3485
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/12595915
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/11259552 http://www.abcam.com/zoniporide-hydrochloride-ab142012.html

Zoniporide hydrochloride is a novel, potent and selective NHE-1 inhibitor (IC50 = 14 nM). Reduces infarct size in the isolated heart (EC50 = 0.25 nM). Attenuates post-ischemic cardiac contractile dysfunction and ischemia-reperfusion-induced ventricular fibrillation in vivo. Zoniporide hydrochloride represents a novel class of potent and selective human NHE-1 inhibitors with potential utility for providing cardioprotection in a clinical setting.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Sodium/hydrogen exchanger 2 9 Target ID: CHEMBL3133 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12595915	Inhibitor 8297		12000.0 nM [IC50]
Sodium/hydrogen exchanger 1 12 Target ID: CHEMBL2781 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12595915 \| https://www.ncbi.nlm.nih.gov/pubmed/12223226	Inhibitor 8297		14.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Cardiovascular diseases 71 Sources: http://adisinsight.springer.com/drugs/800018057 https://www.ncbi.nlm.nih.gov/pubmed/12595915 https://www.ncbi.nlm.nih.gov/pubmed/11259552	Primary		Phase II 1132	Unknown Approved Use Unknown

AUC

Value	Dose	Co-administered	Analyte	Population
0.07 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/11277524	1 mg/kg single, intravenous dose: 1 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		ZONIPORIDE plasma	Rattus norvegicus population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
0.5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/11277524	1 mg/kg single, intravenous dose: 1 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		ZONIPORIDE plasma	Rattus norvegicus population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
46% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/11277524	1 mg/kg single, intravenous dose: 1 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		ZONIPORIDE plasma	Rattus norvegicus population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
12 mg/kg 1 times / day multiple, intravenous Highest studied dose Dose: 12 mg/kg, 1 times / day Route: intravenous Route: multiple Dose: 12 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573	unhealthy, ADULT n = 266 Health Status: unhealthy Condition: peripheral vascular disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 266 Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573	Disc. AE: Hepatic failure, Bilirubin elevated... Other AEs: Headache, Atrial fibrillation... AEs leading to discontinuation/dose reduction: Hepatic failure (0.8%) Bilirubin elevated Vomiting (25.6%) Other AEs: Headache (6.4%) Atrial fibrillation (6.4%) Tachycardia (10.9%) Jaundice (2.3%) Nausea (41.7%) Elevated liver enzyme levels Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573

AEs

AE	Significance	Dose	Population
Elevated liver enzyme levels		12 mg/kg 1 times / day multiple, intravenous Highest studied dose Dose: 12 mg/kg, 1 times / day Route: intravenous Route: multiple Dose: 12 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573	unhealthy, ADULT n = 266 Health Status: unhealthy Condition: peripheral vascular disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 266 Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573
Hepatic failure	0.8% Disc. AE	12 mg/kg 1 times / day multiple, intravenous Highest studied dose Dose: 12 mg/kg, 1 times / day Route: intravenous Route: multiple Dose: 12 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573	unhealthy, ADULT n = 266 Health Status: unhealthy Condition: peripheral vascular disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 266 Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573
Tachycardia	10.9%	12 mg/kg 1 times / day multiple, intravenous Highest studied dose Dose: 12 mg/kg, 1 times / day Route: intravenous Route: multiple Dose: 12 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573	unhealthy, ADULT n = 266 Health Status: unhealthy Condition: peripheral vascular disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 266 Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573
Jaundice	2.3%	12 mg/kg 1 times / day multiple, intravenous Highest studied dose Dose: 12 mg/kg, 1 times / day Route: intravenous Route: multiple Dose: 12 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573	unhealthy, ADULT n = 266 Health Status: unhealthy Condition: peripheral vascular disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 266 Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573
Vomiting	25.6% Disc. AE	12 mg/kg 1 times / day multiple, intravenous Highest studied dose Dose: 12 mg/kg, 1 times / day Route: intravenous Route: multiple Dose: 12 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573	unhealthy, ADULT n = 266 Health Status: unhealthy Condition: peripheral vascular disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 266 Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573
Nausea	41.7%	12 mg/kg 1 times / day multiple, intravenous Highest studied dose Dose: 12 mg/kg, 1 times / day Route: intravenous Route: multiple Dose: 12 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573	unhealthy, ADULT n = 266 Health Status: unhealthy Condition: peripheral vascular disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 266 Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573
Atrial fibrillation	6.4%	12 mg/kg 1 times / day multiple, intravenous Highest studied dose Dose: 12 mg/kg, 1 times / day Route: intravenous Route: multiple Dose: 12 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573	unhealthy, ADULT n = 266 Health Status: unhealthy Condition: peripheral vascular disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 266 Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573
Headache	6.4%	12 mg/kg 1 times / day multiple, intravenous Highest studied dose Dose: 12 mg/kg, 1 times / day Route: intravenous Route: multiple Dose: 12 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573	unhealthy, ADULT n = 266 Health Status: unhealthy Condition: peripheral vascular disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 266 Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573
Bilirubin elevated	Disc. AE	12 mg/kg 1 times / day multiple, intravenous Highest studied dose Dose: 12 mg/kg, 1 times / day Route: intravenous Route: multiple Dose: 12 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573	unhealthy, ADULT n = 266 Health Status: unhealthy Condition: peripheral vascular disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 266 Sources: https://pubmed.ncbi.nlm.nih.gov/16202888 Page: p.573

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	P-gp 1537 AO 16

Drug as perpetrator

Target	Modality	Activity
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=363680395	no
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=363680395	no
CYP3A4 1925	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=363680395	no

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1537	substrate 3367 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363680395	no
AO 16	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23046389/	yes [Km 3.4 uM]

PubMed

Title	Date	PubMed
A novel sodium-hydrogen exchanger isoform-1 inhibitor, zoniporide, reduces ischemic myocardial injury in vitro and in vivo.	2001 Apr	11259552
Discovery of zoniporide: a potent and selective sodium-hydrogen exchanger type 1 (NHE-1) inhibitor with high aqueous solubility.	2001 Mar 26	11277524
Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility.	2002 Sep 6	12215493
Zoniporide: a potent and selective inhibitor of the human sodium-hydrogen exchanger isoform 1 (NHE-1).	2003 Spring	12595915
Initial rate analysis of zoniporide hydrolysis degradants using high-performance liquid chromatography coupled with mass spectrometric detection.	2007	17613888
Solute diffusion through stripped mouse duodenum.	2007 Dec	18195487
Zoniporide preserves left ventricular compliance during ventricular fibrillation and minimizes postresuscitation myocardial dysfunction through benefits on energy metabolism.	2007 Oct	17944021
The rise of [Na(+)] (i) during ischemia and reperfusion in the rat heart-underlying mechanisms.	2007 Sep	17356886
Does the use of a volatile anesthetic regimen attenuate the incidence of cardiac events after vascular surgery?	2008	18468013
Na+/H+ exchanger-1 inhibitors reduce neuronal excitability and alter na+ channel inactivation properties in rat primary sensory neurons.	2008 Jun	18319243
Paradoxical resistance to myocardial ischemia and age-related cardiomyopathy in NHE1 transgenic mice: a role for ER stress?	2009 Feb	19027022
Effects of KR-33028, a novel Na+/H+ exchanger-1 inhibitor, on glutamate-induced neuronal cell death and ischemia-induced cerebral infarct.	2009 Jan 12	19022230
Cross-species comparison of the metabolism and excretion of zoniporide: contribution of aldehyde oxidase to interspecies differences.	2010 Apr	20040581
In vitro-in vivo correlation for intrinsic clearance for drugs metabolized by human aldehyde oxidase.	2010 Aug	20444863
Role of the spinal Na+/H+ exchanger in formalin-induced nociception.	2011 Aug 21	21763398
Critical role of the STAT3 pathway in the cardioprotective efficacy of zoniporide in a model of myocardial preservation - the rat isolated working heart.	2011 Feb	20942815

Patents

Sample Use Guides

In Vivo Use Guide

Rabbits: 0.25, 1, and 4 mg/kg/h, i.v.

Route of Administration: Intravenous

In Vitro Use Guide

Zoniporide inhibited 22Na(+) uptake in fibroblasts expressing human NHE-1 in a concentration-dependent manner (IC(50) = 14 nM)

Substance Class	Chemical Created by `admin` on `Fri Dec 15 15:49:32 UTC 2023` Edited by `admin` on `Fri Dec 15 15:49:32 UTC 2023`
Record UNII	8841R2UJPG
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

ZONIPORIDE

Official Name

English

zoniporide [INN]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C47793