U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C29H38FN3O3.2ClH
Molecular Weight 568.5516
Optical Activity UNSPECIFIED
Defined Stereocenters 2 / 2
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of MIBEFRADIL DIHYDROCHLORIDE

SMILES

CC(C)[C@@]1([H])c2ccc(cc2CC[C@@]1(CCN(C)CCCc3[nH]c4ccccc4n3)OC(=O)COC)F.Cl.Cl

InChI

InChIKey=MTJLQTFHJIHXIX-GDUXWEAWSA-N
InChI=1S/C29H38FN3O3.2ClH/c1-20(2)28-23-12-11-22(30)18-21(23)13-14-29(28,36-27(34)19-35-4)15-17-33(3)16-7-10-26-31-24-8-5-6-9-25(24)32-26;;/h5-6,8-9,11-12,18,20,28H,7,10,13-17,19H2,1-4H3,(H,31,32);2*1H/t28-,29-;;/m0../s1

HIDE SMILES / InChI
Mibefradil is a calcium channel blocker, chemically unlike other compounds in the class, that was approved by the Food and Drug Administration (FDA), U.S.A. in June 1997 for the treatment of patients with hypertension and chronic stable angina. Shortly following its introduction, mibefradil was withdrawn from the market in the U.S.A. as well as in Europe. The reason for the voluntary withdrawal of the drug by Roche laboratories was claimed to be the result of new information about potentially harmful interactions with other drugs. Mibefradil is calcium channel blocker with moderate selectivity for T-type Ca2+ channels displaying IC50 values of 2.7 uM and 18.6 uM for T-type and L-type channels respectively. Mibefradil is a tetralol calcium channel blocking agent that inhibits the influx of calcium ions across both the T (low-voltage) and L (high-voltage) calcium channels of cardiac and vascular smooth muscle, with a greater selectivity for T channels. Vasodilation occurs in vascular smooth muscle, causing a decrease in peripheral vascular resistance and a resulting decrease in blood pressure. Mibefradil causes a slight increase in cardiac output during chronic dosing. Mibefradil slows sinus and atrioventricular (AV) node conduction, producing a slight reduction in heart rate and a slight increase in the PR interval. It has also been shown to slightly lengthen the corrected sinus node recovery time and AH interval and to raise the Wenckebach point. The mechanism by which mibefradil reduces angina is not known, but is thought to be attributed to a reduction in heart rate, total peripheral resistance (afterload), and the heart rate-systolic blood pressure product at any given level of exercise. The result of these effects is a decrease in cardiac workload and myocardial oxygen demand. Mibefradil has been repurposed from an abandoned antihypertensive to a targeted solid tumor treatment, and it has been rescued from drug-drug interactions by using short-term dose exposure. Tau is using the early success of mibefradil as a proof of concept to build a platform technology of Cav3 blockers for broad antitumor applications in combination with new targeted cancer therapies, well-established.

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Posicor

Approved Use

Treatment of hypertension, angina pectoris

Launch Date

8.7039358E11
Primary
Posicor

Approved Use

Treatment of hypertension, angina pectoris

Launch Date

8.7039358E11
Primary
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
718 ng/mL
100 mg 1 times / day steady-state, oral
dose: 100 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
MIBEFRADIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
495 ng/mL
120 mg single, oral
dose: 120 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
MIBEFRADIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
61 ng/mL
80 mg single, oral
dose: 80 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
MIBEFRADIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
777 ng/mL
160 mg single, oral
dose: 160 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
MIBEFRADIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
115 ng/mL
40 mg single, oral
dose: 40 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
MIBEFRADIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
12574 ng × h/mL
100 mg 1 times / day steady-state, oral
dose: 100 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
MIBEFRADIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
35.4 h
100 mg 1 times / day steady-state, oral
dose: 100 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
MIBEFRADIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
13.2 h
120 mg single, oral
dose: 120 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
MIBEFRADIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
14.9 h
80 mg single, oral
dose: 80 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
MIBEFRADIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
17.1 h
160 mg single, oral
dose: 160 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
MIBEFRADIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
9.8 h
40 mg single, oral
dose: 40 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
MIBEFRADIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
0.5%
100 mg 1 times / day steady-state, oral
dose: 100 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
MIBEFRADIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
0.5%
120 mg single, oral
dose: 120 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
MIBEFRADIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
0.5%
80 mg single, oral
dose: 80 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
MIBEFRADIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
0.5%
160 mg single, oral
dose: 160 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
MIBEFRADIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
0.5%
40 mg single, oral
dose: 40 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
MIBEFRADIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
Doses

Doses

DosePopulationAdverse events​
87.5 mg 4 times / day steady, oral
MTD
Dose: 87.5 mg, 4 times / day
Route: oral
Route: steady
Dose: 87.5 mg, 4 times / day
Sources:
unhealthy, 19.8 - 80.5 years
n = 27
Health Status: unhealthy
Condition: High-grade gliomas
Age Group: 19.8 - 80.5 years
Sex: M+F
Population Size: 27
Sources:
DLT: Alanine aminotransferase increased, Aspartate aminotransferase increased...
Dose limiting toxicities:
Alanine aminotransferase increased (grade 3, 1 patient)
Aspartate aminotransferase increased (grade 3, 1 patient)
Sinus bradycardia (grade 1, 1 patient)
Sources:
AEs

AEs

AESignificanceDosePopulation
Sinus bradycardia grade 1, 1 patient
DLT, Disc. AE
87.5 mg 4 times / day steady, oral
MTD
Dose: 87.5 mg, 4 times / day
Route: oral
Route: steady
Dose: 87.5 mg, 4 times / day
Sources:
unhealthy, 19.8 - 80.5 years
n = 27
Health Status: unhealthy
Condition: High-grade gliomas
Age Group: 19.8 - 80.5 years
Sex: M+F
Population Size: 27
Sources:
Alanine aminotransferase increased grade 3, 1 patient
DLT, Disc. AE
87.5 mg 4 times / day steady, oral
MTD
Dose: 87.5 mg, 4 times / day
Route: oral
Route: steady
Dose: 87.5 mg, 4 times / day
Sources:
unhealthy, 19.8 - 80.5 years
n = 27
Health Status: unhealthy
Condition: High-grade gliomas
Age Group: 19.8 - 80.5 years
Sex: M+F
Population Size: 27
Sources:
Aspartate aminotransferase increased grade 3, 1 patient
DLT, Disc. AE
87.5 mg 4 times / day steady, oral
MTD
Dose: 87.5 mg, 4 times / day
Route: oral
Route: steady
Dose: 87.5 mg, 4 times / day
Sources:
unhealthy, 19.8 - 80.5 years
n = 27
Health Status: unhealthy
Condition: High-grade gliomas
Age Group: 19.8 - 80.5 years
Sex: M+F
Population Size: 27
Sources:
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG


OverviewOther

Other InhibitorOther SubstrateOther Inducer





Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no
yes [IC50 0.8 uM]
yes (co-administration study)
Comment: Coadministration of mibefradil increased the Cmax of midazolam 3-fold, the AUC 8- to 9-fold, and the t1/2 4-fold
yes [IC50 1.6 uM]
yes
yes
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
yes
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
The evaluation of pharmacologic therapy in humans: a brief summary of the drug evaluation process and guidelines for clinical trials as they related to women.
2001
Role of membrane depolarization and T-type Ca2+ channels in angiotensin II and K+ stimulated aldosterone secretion.
2001 Apr 25
The underreporting of results and possible mechanisms of 'negative' drug trials in patients with chronic heart failure.
2001 Aug
Selectivity of blocking of low- versus high-voltage activated calcium currents by the dihydropyridine derivatives Bay E5759 and Bay A4339 in neuroblastoma--glioma NG 108-15 cells.
2001 Aug
The triakontatetraneuropeptide TTN increases [CA2+]i in rat astrocytes through activation of peripheral-type benzodiazepine receptors.
2001 Aug
Emerging role of drug interaction studies in drug development: the good, the bad, and the unknown.
2001 Autumn
Comparison of L-type and mixed L- and T-type calcium channel blockers on kidney injury caused by deoxycorticosterone-salt hypertension in rats.
2001 Dec
Effects of mibefradil, a T- and L-type calcium channel blocker, on cardiac remodeling in the UM-X7.1 cardiomyopathic hamster.
2001 Jan
Inhibition of lens epithelial cell adhesion by the calcium antagonist Mibefradil correlates with impaired integrin distribution and organization of the cytoskeleton.
2001 Jul
L-type and T-type calcium channel blockade potentiate the analgesic effects of morphine and selective mu opioid agonist, but not to selective delta and kappa agonist at the level of the spinal cord in mice.
2001 Jul
Redox modulation of T-type calcium channels in rat peripheral nociceptors.
2001 Jul 19
Inhibition of T-type and L-type calcium channels by mibefradil: physiologic and pharmacologic bases of cardiovascular effects.
2001 Jun
Novel voltage-dependent non-selective cation conductance in murine colonic myocytes.
2001 Jun 1
Comparison of sympathetic modulation induced by single oral doses of mibefradil, amlodipine, and nifedipine in healthy volunteers.
2001 Mar
Inhibitory effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes.
2001 May
Comparative effects of selective T- and L-type calcium channel blockers in the remnant kidney model.
2001 May
Blocking swelling-activated chloride current inhibits mouse liver cell proliferation.
2001 May 1
Divergent renal vasodilator action of L- and T-type calcium antagonists in vivo.
2001 Nov
State-dependent inhibition of inactivation-deficient Ca(V)1.2 and Ca(V)2.3 channels by mibefradil.
2001 Nov 15
Torsades de pointes caused by Mibefradil.
2001 Oct
Antioxidant effect of T-type calcium channel blockers in gastric injury.
2002 Apr
Neuronal T-type alpha 1H calcium channels induce neuritogenesis and expression of high-voltage-activated calcium channels in the NG108-15 cell line.
2002 Aug 15
Angiotensin I-converting enzyme inhibition increases cardiac catecholamine content and reduces monoamine oxidase activity via an angiotensin type 1 receptor-mediated mechanism.
2002 Feb
Impaired mechanisms of leukocyte adhesion in vitro by the calcium channel antagonist mibefradil.
2002 May
Mibefradil improves beta-adrenergic responsiveness and intracellular Ca(2+) handling in hypertrophied rat myocardium.
2002 May
Selective coupling of T-type calcium channels to SK potassium channels prevents intrinsic bursting in dopaminergic midbrain neurons.
2002 May 1
Involvement of T-type calcium channels in excitatory junction potentials in rat resistance mesenteric arteries.
2002 Nov
Ca2+ entry via P/Q-type Ca2+ channels and the Na+/Ca2+ exchanger in rat and human neocortical synaptosomes.
2002 Nov
Calcium channel blockade limits transcriptional, translational and functional up-regulation of the cardiac calpain system after myocardial infarction.
2002 Oct 18
Cellular mechanism for mibefradil-induced vasodilation of renal microcirculation: studies in the isolated perfused hydronephrotic kidney.
2003 Dec
Effects of first and second generation calcium channel blockers on diastolic function of the failing hamster heart: relationship with coronary flow changes.
2003 Jul
A T-type calcium channel required for normal function of a mammalian mechanoreceptor.
2003 Jul
The influence of calcium channel antagonists on isolated human distal radial arteries.
2003 Nov
Mechanism of active repolarization of inhibitory junction potential in murine colon.
2003 Nov
Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia.
2003 Nov 17
Thalamic control of visceral nociception mediated by T-type Ca2+ channels.
2003 Oct 3
T-type calcium channels in the regulation of afferent and efferent arterioles in rats.
2004 Feb
Patents

Patents

Sample Use Guides

50 mg once daily, increased if necessary.
Route of Administration: Oral
Mibefradil (3 uM) inhibited the excitatory junction potentials (EJPs) in rat resistance mesenteric arteries by about 50%.
Name Type Language
MIBEFRADIL DIHYDROCHLORIDE
MI   USAN   VANDF  
USAN  
Official Name English
POSICOR
Brand Name English
MIBEFRADIL HYDROCHLORIDE
MART.   WHO-DD  
Common Name English
(1S,2S)-(2-((3-(2-BENZIMIDAZOLYL)PROPYL)METHYLAMINO)ETHYL)-6-FLUORO-1,2,3,4-TETRAHYDRO-1-ISOPROPYL-2-NAPHTHYL METHOXYACETATE, DIHYDROCHLORIDE
Common Name English
MIBEFRADIL DIHYDROCHLORIDE [MI]
Common Name English
MIBEFRADIL DIHYDROCHLORIDE [VANDF]
Common Name English
ACETIC ACID, METHOXY-, 2-(2-((3-(1H-BENZIMIDAZOL-2-YL)PROPYL)METHYLAMINO)ETHYL)-6-FLUORO-1,2,3,4-TETRAHYDRO-1-(1-METHYLETHYL)-2-NAPHTHALENYL ESTER, DIHYDROCHLORIDE, (1S-CIS)-
Common Name English
RO 40-5967/001
Code English
MIBEFRADIL HYDROCHLORIDE [WHO-DD]
Common Name English
MIBEFRADIL DIHYDROCHLORIDE [USAN]
Common Name English
MIBEFRADIL HYDROCHLORIDE [MART.]
Common Name English
RO-40-5967/001
Code English
Classification Tree Code System Code
NCI_THESAURUS C333
Created by admin on Sat Jun 26 07:53:02 UTC 2021 , Edited by admin on Sat Jun 26 07:53:02 UTC 2021
Code System Code Type Description
ChEMBL
CHEMBL45816
Created by admin on Sat Jun 26 07:53:02 UTC 2021 , Edited by admin on Sat Jun 26 07:53:02 UTC 2021
PRIMARY
EPA CompTox
116666-63-8
Created by admin on Sat Jun 26 07:53:02 UTC 2021 , Edited by admin on Sat Jun 26 07:53:02 UTC 2021
PRIMARY
RXCUI
83214
Created by admin on Sat Jun 26 07:53:02 UTC 2021 , Edited by admin on Sat Jun 26 07:53:02 UTC 2021
PRIMARY RxNorm
FDA UNII
842TUP3PQ8
Created by admin on Sat Jun 26 07:53:02 UTC 2021 , Edited by admin on Sat Jun 26 07:53:02 UTC 2021
PRIMARY
MERCK INDEX
M7522
Created by admin on Sat Jun 26 07:53:02 UTC 2021 , Edited by admin on Sat Jun 26 07:53:02 UTC 2021
PRIMARY Merck Index
CAS
116666-63-8
Created by admin on Sat Jun 26 07:53:02 UTC 2021 , Edited by admin on Sat Jun 26 07:53:02 UTC 2021
PRIMARY
DRUG BANK
DBSALT002896
Created by admin on Sat Jun 26 07:53:02 UTC 2021 , Edited by admin on Sat Jun 26 07:53:02 UTC 2021
PRIMARY
NCI_THESAURUS
C87687
Created by admin on Sat Jun 26 07:53:02 UTC 2021 , Edited by admin on Sat Jun 26 07:53:02 UTC 2021
PRIMARY
PUBCHEM
60662
Created by admin on Sat Jun 26 07:53:02 UTC 2021 , Edited by admin on Sat Jun 26 07:53:02 UTC 2021
PRIMARY
EVMPD
SUB20668
Created by admin on Sat Jun 26 07:53:02 UTC 2021 , Edited by admin on Sat Jun 26 07:53:02 UTC 2021
PRIMARY