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Details

Stereochemistry ABSOLUTE
Molecular Formula C29H38FN3O3
Molecular Weight 495.6287
Optical Activity UNSPECIFIED
Defined Stereocenters 2 / 2
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of MIBEFRADIL

SMILES

COCC(=O)O[C@]3(CCN(C)CCCC1=NC2=CC=CC=C2N1)CCC4=CC(F)=CC=C4[C@@H]3C(C)C

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

Molecular Formula C29H38FN3O3
Molecular Weight 495.6287
Charge 0
Count
MOL RATIO 1 MOL RATIO (average)
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 2 / 2
E/Z Centers 0
Optical Activity UNSPECIFIED

Description

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 Shortly following its introduction, mibefradil was withdrawn from the market in the U.S.A. as well as in Europe.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.

CNS Activity

Originator

Approval Year

Targets

Primary TargetPharmacologyConditionPotency
32.0 nM [IC50]
1.34 µM [IC50]
202.0 nM [IC50]
126.0 nM [IC50]

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Posicor
Primary
Posicor
Primary
Unknown

Cmax

ValueDoseCo-administeredAnalytePopulation
718 ng/mL
100 mg 1 times / day steady-state, oral
MIBEFRADIL plasma
Homo sapiens
495 ng/mL
120 mg single, oral
MIBEFRADIL plasma
Homo sapiens
61 ng/mL
80 mg single, oral
MIBEFRADIL plasma
Homo sapiens
777 ng/mL
160 mg single, oral
MIBEFRADIL plasma
Homo sapiens
115 ng/mL
40 mg single, oral
MIBEFRADIL plasma
Homo sapiens

AUC

ValueDoseCo-administeredAnalytePopulation
12574 ng × h/mL
100 mg 1 times / day steady-state, oral
MIBEFRADIL plasma
Homo sapiens

T1/2

ValueDoseCo-administeredAnalytePopulation
35.4 h
100 mg 1 times / day steady-state, oral
MIBEFRADIL plasma
Homo sapiens
13.2 h
120 mg single, oral
MIBEFRADIL plasma
Homo sapiens
14.9 h
80 mg single, oral
MIBEFRADIL plasma
Homo sapiens
17.1 h
160 mg single, oral
MIBEFRADIL plasma
Homo sapiens
9.8 h
40 mg single, oral
MIBEFRADIL plasma
Homo sapiens

Funbound

ValueDoseCo-administeredAnalytePopulation
0.5%
100 mg 1 times / day steady-state, oral
MIBEFRADIL plasma
Homo sapiens
0.5%
120 mg single, oral
MIBEFRADIL plasma
Homo sapiens
0.5%
80 mg single, oral
MIBEFRADIL plasma
Homo sapiens
0.5%
160 mg single, oral
MIBEFRADIL plasma
Homo sapiens
0.5%
40 mg single, oral
MIBEFRADIL plasma
Homo sapiens

Doses

AEs

Overview

CYP3A4CYP2C9CYP2D6hERG


OverviewOther

Other InhibitorOther SubstrateOther Inducer





Drug as perpetrator​

Drug as victim

Tox targets

PubMed

Patents

Sample Use Guides

In Vivo Use Guide
50 mg once daily, increased if necessary.
Route of Administration: Oral
In Vitro Use Guide
Mibefradil (3 uM) inhibited the excitatory junction potentials (EJPs) in rat resistance mesenteric arteries by about 50%.
Substance Class Chemical
Record UNII
27B90X776A
Record Status Validated (UNII)
Record Version