CLOFILIUM PHOSPHATE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C21H37ClN.H2O4P
Molecular Weight	435.965
Optical Activity	NONE
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OP(O)([O-])=O.CCCCCCC[N+](CC)(CC)CCCCC1=CC=C(Cl)C=C1

InChI

InChIKey=HBLQZEWZVJXHKQ-UHFFFAOYSA-M

InChI=1S/C21H37ClN.H3O4P/c1-4-7-8-9-11-18-23(5-2,6-3)19-12-10-13-20-14-16-21(22)17-15-20;1-5(2,3)4/h14-17H,4-13,18-19H2,1-3H3;(H3,1,2,3,4)/q+1;/p-1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/6881021 | https://www.ncbi.nlm.nih.gov/pubmed/6692647 | https://www.ncbi.nlm.nih.gov/pubmed/9315735

Clofilium is a quaternary ammonium compound that acts as potassium channel blocker. Clofilium is a class III agent. Clofilium increases atrial and ventricular effective refractory period without changing conduction time and, despite no apparent change in premature ventricular complex frequency, it can abolish the ability to induce ventricular tachycardia by programmed stimulation and is also well tolerated.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
HERG 99 Target ID: CHEMBL240 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24224763 \| https://www.ncbi.nlm.nih.gov/pubmed/16155403 \| https://www.ncbi.nlm.nih.gov/pubmed/23271893 \|	Blocker 555	2.0 nM [IC50]
Potassium channel subfamily T member 1 7 Target ID: Q5JUK3 Gene ID: 57582.0 Gene Symbol: KCNT1 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/23271893	Blocker 555
Potassium voltage-gated channel subfamily H member 1 3 Target ID: O95259 Gene ID: 3756.0 Gene Symbol: KCNH1 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/23271893	Blocker 555	255.0 nM [IC50]
Voltage-gated potassium channel subunit Kv1.5 43 Target ID: CHEMBL4306 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23271893 \| https://www.ncbi.nlm.nih.gov/pubmed/7838129	Blocker 555	840.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Cardiac arrhythmia 19 Sources: https://www.ncbi.nlm.nih.gov/pubmed/28011953 https://www.ncbi.nlm.nih.gov/pubmed/9064988	Primary		Phase I 438	Unknown Approved Use Unknown

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
			inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
rOCT1 3 rOATP1B1/3 3

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
rOATP1B1/3 3	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/20381614/	yes [Inhibition 20 uM]
rOCT1 3	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/20381614/	yes [Inhibition 20 uM]

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://pubmed.ncbi.nlm.nih.gov/12522086/

PubMed

Title	Date	PubMed
Modulation of drug block of the cardiac potassium channel KCNA5 by the drug transporters OCTN1 and MDR1.	2010-11	20977453
Activation of the TASK-2 channel after cell swelling is dependent on tyrosine phosphorylation.	2010-10	20631251
Emerging treatments in the management of schizophrenia - focus on sertindole.	2010-09-07	20856845
K+ channel openers restore verapamil-inhibited lung fluid resolution and transepithelial ion transport.	2010-05-27	20507598
Endogenous purinergic signaling is required for osmotic volume regulation of retinal glial cells.	2010-03	20002522
Uni- or bi-ventricular hypertrophy and susceptibility to drug-induced torsades de pointes.	2010-01-30	20435152
Stereoselective Inhibition of the hERG1 Potassium Channel.	2010	21833176
Involvement of A(1) adenosine receptors in osmotic volume regulation of retinal glial cells in mice.	2009-09-12	19756184
UTP regulation of ion transport in alveolar epithelial cells involves distinct mechanisms.	2009-09	19542245
ROS activate KCl cotransport in nonadherent Ehrlich ascites cells but K+ and Cl- channels in adherent Ehrlich Lettré and NIH3T3 cells.	2009-07	19419998
Pharmacological characteristics and clinical applications of K201.	2009-05	19442077
Molecular determinants of hERG channel block by terfenadine and cisapride.	2008-11	18987434
Dual pathway activated by tert-butyl hydroperoxide in human airway anion secretion.	2008-11	18664589
Importance of vagally mediated bradycardia for the induction of torsade de pointes in an in vivo model.	2008-07	18587444
Water and ion channels: crucial in the initiation and progression of apoptosis in central nervous system?	2008-06	19305791
Antitorsadogenic effects of ({+/-})-N-(2,6-dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine (ranolazine) in anesthetized rabbits.	2008-06	18322148
A gender-independent proarrhythmic action of 17beta-estradiol in anaesthetized rabbits.	2007-12-01	17692839
Involvement of KATP and KvLQT1 K+ channels in EGF-stimulated alveolar epithelial cell repair processes.	2007-10	17631610
Inhibition of the HERG potassium channel by the tricyclic antidepressant doxepin.	2007-08-01	17560554
K201, a multi-channel blocker, inhibits clofilium-induced torsades de pointes and attenuates an increase in repolarization.	2007-01-19	17112502
Arrhythmogenic mechanisms in the isolated perfused hypokalaemic murine heart.	2007-01	17280555
5-Azacytidine induces changes in electrophysiological properties of human mesenchymal stem cells.	2006-12	17160070
Regulation of ENaC and CFTR expression with K+ channel modulators and effect on fluid absorption across alveolar epithelial cells.	2006-12	16891388
Distinct K+ conductive pathways are required for Cl- and K+ secretion across distal colonic epithelium.	2006-10	16641164
Use of a failing rabbit heart as a model to predict torsadogenicity.	2006-09	16740615
RSD1235 blocks late INa and suppresses early afterdepolarizations and torsades de pointes induced by class III agents.	2006-06-01	16545351
New insights about HERG blockade obtained from protein modeling, potential energy mapping, and docking studies.	2006-05-01	16413785
The role of late I and antiarrhythmic drugs in EAD formation and termination in Purkinje fibers.	2006-05	16686685
Functional IsK/KvLQT1 potassium channel in a new corticosteroid-sensitive cell line derived from the inner ear.	2006-04-14	16478723
Investigation of the role of TASK-2 channels in rat pulmonary arteries; pharmacological and functional studies following RNA interference procedures.	2006-03	16432512
Two-pore-domain potassium channels support anion secretion from human airway Calu-3 epithelial cells.	2006-02	16311719
Drug binding interactions in the inner cavity of HERG channels: molecular insights from structure-activity relationships of clofilium and ibutilide analogs.	2006-02	16291873
Tandem-pore domain potassium channels are functionally expressed in retinal (Müller) glial cells.	2006-02	16265669
Characterization of potassium channels involved in volume regulation of human spermatozoa.	2005-12	16421215
hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines.	2005-10-03	16175187
In vivo targeting of ERG potassium channels in mice and dogs by a positron-emitting analogue of fluoroclofilium.	2005-08-31	16155403
The effects of putative K+ channel blockers on volume regulation of murine spermatozoa.	2005-05	15673604
Inhibitory effects of clofilium on membrane currents associated with Ca channels, NMDA receptor channels and Na+, K+-ATPase in cortical neurons.	2005-03	15637453
Volume regulation of mature and immature spermatozoa in a primate model, and possible ion channels involved.	2004-11	15319384
Structural determinants of HERG channel block by clofilium and ibutilide.	2004-08	15266014
Effects of chloride and potassium channel blockers on apoptotic cell shrinkage and apoptosis in cortical neurons.	2004-06	15057559
Volume changes and whole cell membrane currents activated during gradual osmolarity decrease in C6 glioma cells: contribution of two types of K+ channels.	2004-06	14736709
Molecular determinants for high-affinity block of human EAG potassium channels by antiarrhythmic agents.	2004-05	15102940
Functional evidence of a role for two-pore domain potassium channels in rat mesenteric and pulmonary arteries.	2004-05	15066906
Volume regulation is defective in renal proximal tubule cells isolated from KCNE1 knockout mice.	2004-03	15123546
Drug-related torsades de pointes in the isolated rabbit heart: comparison of clofilium, d,l-sotalol, and erythromycin.	1998-09	9733356
Mechanism of clofilium block of the human Kv1.5 delayed rectifier potassium channel.	1995-01	7838129
Cloning, expression, pharmacology and regulation of a delayed rectifier K+ channel in mouse heart.	1991-10	1655403
Broad sensitivity of rodent arrhythmia models to class I, II, III, and IV antiarrhythmic agents.	1989-06	2726785
Effects of antiarrhythmic agents on isoproterenol-induced ventricular fibrillation in heavy rats: a possible model of sudden cardiac death.	1986-03	3704313

Patents

Sample Use Guides

In Vivo Use Guide

Eight dogs were given clofilium phosphate (0.34 mg/kg, iv). The maximum clofilium effect was a 31% decrease in threshold current and a 54% decrease in threshold energy.

Route of Administration: Intravenous

In Vitro Use Guide

Clofilium at < or = 10(-6) M had no effect on WKY portal vein contractions and at < or = 3 x 10(-4) M had no effect on WKY or SHR quiescent mesenteric and intralobar pulmonary arteries. 3. Clofilium at 10(7) - 10(-5) M prolonged the WKY left ventricular action potentials and with 10(-6) and 10(-5)M this included after-depolarizations. 4. Clofilium at < or = 3 x 10(-5) M augmented the peak force, prolonged the contractions and did not cause arrhythmias in the absence and presence of isoprenaline on left ventricle strips from 12-month-old WKY.

Name

Type

Language

LY 150378

Preferred Name

English

CLOFILIUM PHOSPHATE

Official Name

English

LY-150378

Code

English

(4-(P-CHLOROPHENYL)BUTYL)DIETHYLHEPTYLAMMONIUM PHOSPHATE (1:1)

Common Name

English

CLOFILIUM PHOSPHATE [MART.]

Common Name

English

CLOFILIUM PHOSPHATE [USAN]

Common Name

English

clofilium phosphate [INN]

Common Name

English

BENZENEBUTANAMINIUM, 4-CHLORO-N,N-DIETHYL-N-HEPTYL-, PHOSPHATE (1:1)

Systematic Name

English

Classification Tree Code System Code

NCI_THESAURUS

C47793