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

Details

Stereochemistry ABSOLUTE
Molecular Formula C29H38FN3O3
Molecular Weight 495.6298
Optical Activity UNSPECIFIED
Defined Stereocenters 2 / 2
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of MIBEFRADIL

SMILES

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

InChI

InChIKey=HBNPJJILLOYFJU-VMPREFPWSA-N
InChI=1S/C29H38FN3O3/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)/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 Shortly following its introduction, mibefradil was withdrawn from the market in the U.S.A. as well as in Europe.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
Combination of calcium channel blockers and beta blockers for patients with exercise-induced angina pectoris: a double-blind parallel-group comparison of different classes of calcium channel blockers. The Netherlands Working Group on Cardiovascular Research (WCN).
1999 Jun
Role of membrane depolarization and T-type Ca2+ channels in angiotensin II and K+ stimulated aldosterone secretion.
2001 Apr 25
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
Comparative effects of mibefradil and nifedipine gastrointestinal transport system on autonomic function in patients with mild to moderate essential hypertension.
2001 Feb
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
Novel voltage-dependent non-selective cation conductance in murine colonic myocytes.
2001 Jun 1
Perceived benefit after participating in positive or negative/neutral heart failure trials: the patients' perspective.
2001 Mar
State-dependent inhibition of inactivation-deficient Ca(V)1.2 and Ca(V)2.3 channels by mibefradil.
2001 Nov 15
Low threshold T-type calcium current in rat embryonic chromaffin cells.
2001 Nov 15
Torsades de pointes caused by Mibefradil.
2001 Oct
Divergent natriuretic action of calcium channel antagonists in mongrel dogs: renal haemodynamics as a determinant of natriuresis.
2001 Oct
Antioxidant effect of T-type calcium channel blockers in gastric injury.
2002 Apr
Fractal pharmacokinetics of the drug mibefradil in the liver.
2002 Aug
Role of T-type calcium channels in myogenic tone of skeletal muscle resistance arteries.
2002 Dec
An ACTH- and ATP-regulated background K+ channel in adrenocortical cells is TREK-1.
2002 Dec 20
Randomized comparison of T-type versus L-type calcium-channel blockade on exercise duration in stable angina: results of the Posicor Reduction of Ischemia During Exercise (PRIDE) trial.
2002 Jul
T-Type calcium channel alpha1G and alpha1H subunits in human retinoblastoma cells and their loss after differentiation.
2002 Jul
Identification of T-type alpha1H Ca2+ channels (Ca(v)3.2) in major pelvic ganglion neurons.
2002 Jun
Voltage-dependent inward currents of interstitial cells of Cajal from murine colon and small intestine.
2002 Jun 15
Myopathy and rhabdomyolysis with lipid-lowering drugs.
2002 Mar 10
Pharmacological interactions of statins.
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
Acute effects of L- and T-type calcium channel antagonists on cardiovascular reflexes in conscious rabbits.
2002 May-Jun
Involvement of T-type calcium channels in excitatory junction potentials in rat resistance mesenteric arteries.
2002 Nov
Effects of mibefradil on uterine contractility.
2002 Nov 22
Calcium channel blockade limits transcriptional, translational and functional up-regulation of the cardiac calpain system after myocardial infarction.
2002 Oct 18
The sources and sequestration of Ca(2+) contributing to neuroeffector Ca(2+) transients in the mouse vas deferens.
2003 Dec 1
Regulation of ANP secretion by cardiac Na+/Ca2+ exchanger using a new controlled atrial model.
2003 Jan
A T-type calcium channel required for normal function of a mammalian mechanoreceptor.
2003 Jul
Spontaneous regenerative activity in mammalian retinal bipolar cells: roles of multiple subtypes of voltage-dependent Ca2+ channels.
2003 Mar-Apr
Mechanism of active repolarization of inhibitory junction potential in murine colon.
2003 Nov
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
INN   MI   VANDF   WHO-DD  
INN  
Official Name English
MIBEFRADIL [VANDF]
Common Name English
MIBEFRADIL [INN]
Common Name English
MIBEFRADIL [MI]
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, (1S-CIS)-
Common Name English
MIBEFRADIL [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
Systematic Name English
Classification Tree Code System Code
FDA ORPHAN DRUG 224806
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
FDA ORPHAN DRUG 289209
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
FDA ORPHAN DRUG 268608
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
WHO-ATC C08CX01
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
NCI_THESAURUS C333
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
WHO-VATC QC08CX01
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
Code System Code Type Description
EVMPD
SUB08940MIG
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
PRIMARY
DRUG CENTRAL
1797
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
PRIMARY
DRUG BANK
DB01388
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
PRIMARY
MESH
D020748
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
PRIMARY
MERCK INDEX
M7522
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
PRIMARY Merck Index
RXCUI
83213
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
PRIMARY RxNorm
FDA UNII
27B90X776A
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
PRIMARY
IUPHAR
2522
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
PRIMARY
CAS
116644-53-2
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
PRIMARY
PUBCHEM
60663
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
PRIMARY
EPA CompTox
116644-53-2
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
PRIMARY
INN
7134
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
PRIMARY
ChEMBL
CHEMBL45816
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
PRIMARY
NCI_THESAURUS
C87686
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
PRIMARY
WIKIPEDIA
MIBEFRADIL
Created by admin on Sat Jun 26 12:12:28 UTC 2021 , Edited by admin on Sat Jun 26 12:12:28 UTC 2021
PRIMARY