MIBEFRADIL

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 Search

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

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/7996461 | https://www.ncbi.nlm.nih.gov/pubmed/21256842 | https://www.fda.gov/ohrms/dockets/ac/98/briefingbook/1998-3454B1_03_WL32.pdf | https://www.drugbank.ca/drugs/DB01388 | https://www.ncbi.nlm.nih.gov/pubmed/26690767

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 Shortly following its introduction, mibefradil was withdrawn from the market in the U.S.A. as well as in Europe.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 Target	Pharmacology	Potency
Voltage-gated T-type calcium channel alpha-1H subunit 7 Target ID: CHEMBL1859 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10991994	Blocker 537	32.0 nM [IC50]
Voltage-gated T-type calcium channel alpha-1G subunit 8 Target ID: CHEMBL4641 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10991994	Blocker 537	1.34 µM [IC50]
Voltage-gated L-type calcium channel alpha-1C subunit 44 Target ID: CHEMBL1940 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10991994	Blocker 537	202.0 nM [IC50]
Voltage-gated T-type calcium channel alpha-1I subunit 4 Target ID: CHEMBL5558 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18817368	Blocker 537	126.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Hypertension 567 Sources: http://adisinsight.springer.com/drugs/800000236 http://www.mims.com/malaysia/drug/info/mibefradil?mtype=generic	Primary	Withdrawn	Posicor Approved Use Treatment of hypertension, angina pectoris Launch Date 1997
Stable angina, chronic 2 Sources: http://adisinsight.springer.com/drugs/800000236 http://www.mims.com/malaysia/drug/info/mibefradil?mtype=generic	Primary	Withdrawn	Posicor Approved Use Treatment of hypertension, angina pectoris Launch Date 1997
Glioblastoma multiforme 30 Sources: https://clinicaltrials.gov/ct2/show/NCT02202993	Primary	Phase I 428	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
718 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9811158	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9811158	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9811158	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9811158	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9811158	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

Value	Dose	Co-administered	Analyte	Population
12574 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9811158	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

T_1/2

Value	Dose	Analyte	Population
35.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9811158	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9811158	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9811158	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9811158	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9811158	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

F_unbound

Value	Dose	Analyte	Population
0.5% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9811158	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% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9811158	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% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9811158	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% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9811158	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% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9811158	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

Dose	Population	Adverse 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: https://pubmed.ncbi.nlm.nih.gov/28371832/	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: https://pubmed.ncbi.nlm.nih.gov/28371832/	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: https://pubmed.ncbi.nlm.nih.gov/28371832/

AEs

AE	Significance	Dose	Population
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: https://pubmed.ncbi.nlm.nih.gov/28371832/	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: https://pubmed.ncbi.nlm.nih.gov/28371832/
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: https://pubmed.ncbi.nlm.nih.gov/28371832/	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: https://pubmed.ncbi.nlm.nih.gov/28371832/
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: https://pubmed.ncbi.nlm.nih.gov/28371832/	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: https://pubmed.ncbi.nlm.nih.gov/28371832/

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
		inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461 CYP3A 214 CYP2C8/9 44 CYP1A2 1524	P-gp 1537

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP2C8/9 44	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014217/	no
CYP3A 298	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/28/8/895;https://pubmed.ncbi.nlm.nih.gov/14517191/	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 Sources: https://dmd.aspetjournals.org/content/28/8/895;https://pubmed.ncbi.nlm.nih.gov/14517191/
P-gp 1650	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/28/8/895	yes [IC50 1.6 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/9620098/	yes
CYP2D6 1891	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/9620098/	yes

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1537	substrate 3367 Sources: https://dmd.aspetjournals.org/content/28/8/895	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://pubmed.ncbi.nlm.nih.gov/9765513/

Sourcing

Vendor/Aggregator	ID	URL
3B Scientific (Wuhan) Corp	3B2-0615	http://www.3bsc.com/index/pro_info.php?id=19971
AA Blocks	AA000CVK	https://www.aablocks.com/goods/Goods/detail?id=AA000CVK
AHH Chemical co.,ltd	API-1585	http://www.ahhchemical.com/product/API-1585.html
AK Scientific, Inc. (AKSCI)	3848AH	http://www.aksci.com/item_detail.php?cat=3848AH
Aaron Chemicals	AR000DNC	http://www.aaronchem.com/116666-63-8
Achemtek	0102-014068	http://www.achemtek.com/116666-63-8
Ambeed	A186181	https://www.ambeed.com/products/116666-63-8.html
Ambinter	Amb22388695	http://www.ambinter.com/reference/22388695
AstaTech, Inc.	FD5011	http://www.astatechinc.com/CPSResult.php?CRNO=37150
Aurora Fine Chemicals LLC	A18.033.557	http://online.aurorafinechemicals.com/info?ID=A18.033.557
Aurora Fine Chemicals LLC	K16.774.691	http://online.aurorafinechemicals.com/info?ID=K16.774.691
BLD Pharm	BD140109	http://www.bldpharm.com/products/116666-63-8.html
BioChemPartner	BCP15607	http://www.biochempartner.com/116666-63-8-BCP15607
BioCrick	BCC1749	http://www.biocrick.com/Mibefradil-dihydrochloride-BCC1749.html
BioSynth	J-003469	https://www.biosynth.com/en/products/all-products/products/J-003469.html
Boerchem	BC238043	http://www.boerchem.com/?product_43014.html
CSNpharm	CSN11439	https://www.csnpharm.com/products/mibefradil-dihydrochloride.html
Chem Scene	CS-1189	http://www.chemscene.com/116666-63-8.html
ChemMol	97900807	http://www.chemmol.com/chemmol/97900807.html
ChemShuttle	157254	http://www.chemshuttle.com/catalogsearch/result/?q=116666-63-8&cat=
Chemspace	CSSB00000053596	https://chem-space.com/CSSB00000053596
DC Chemicals	DC7463	http://www.dcchemicals.com/product_show-Mibefradil_dihydrochloride.html
Excenen	EX-A2252	https://www.excenen.com/searchresultlist.php?id=116666-63-8
Lab Network	LN01327325	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01327325
Lan Pharmatech	LAN-B69433	http://www.lanpharmatech.com/product-9?_keywords=LAN-B69433
Matrix Scientific	207068	https://www.matrixscientific.com/207068.html
MedChem Express	HY-15553A	https://www.medchemexpress.com/Mibefradil-dihydrochloride.html
MolPort	MolPort-003-666-827	https://www.molport.com/shop/molecule-link/MolPort-003-666-827
MuseChem	I000599	https://www.musechem.com/product/I000599.html
Synblock Inc	SB17509	http://www.synblock.com/product/116666-63-8.html
Tocris	2198	https://www.tocris.com/products/mibefradil-dihydrochloride_2198
Vesino Industrial Co Ltd	VA11293	http://www.vsnchem.com/goto/product/22631/
Yuhao Chemical	CJ3053	http://www.chemyuhao.com/116644-53-2.html
abcr GmbH	AB450277	http://www.abcr.de/shop/en/AB450277
eNovation Chemicals	D372240	https://www.enovationchem.com/ProductDetails.asp?ProductID=D372240
eNovation Chemicals	D501894	https://www.enovationchem.com/ProductDetails.asp?ProductID=D501894

PubMed

Title	Date	PubMed
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	10378820
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	11727466
Low-voltage-activated calcium channels are not involved in capacitation and biological response to progesterone in human sperm.	2001 Dec	11737415
Protective effect of T-type calcium channel blocker in histamine-induced paw inflammation in rat.	2001 Dec	11735361
Conducted vasoconstriction in rat mesenteric arterioles: role for dihydropyridine-insensitive Ca(2+) channels.	2001 Feb	11158955
Effects of the T-type calcium channel blockade with oral mibefradil on the electrophysiologic properties of the human heart.	2001 Jan-Feb	11208497
Inhibition of lens epithelial cell adhesion by the calcium antagonist Mibefradil correlates with impaired integrin distribution and organization of the cytoskeleton.	2001 Jul	11561795
Comparative effects of selective T- and L-type calcium channel blockers in the remnant kidney model.	2001 May	11358939
Evidence against an action of mibefradil at N-type voltage-operated calcium channels.	2001 Nov	11692226
Divergent renal vasodilator action of L- and T-type calcium antagonists in vivo.	2001 Nov	11677369
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	12177183
Selectivity of different calcium antagonists on T- and L-type calcium currents in guinea-pig ventricular myocytes.	2002 Dec	12457621
An ACTH- and ATP-regulated background K+ channel in adrenocortical cells is TREK-1.	2002 Dec 20	12368289
Identification of T-type alpha1H Ca2+ channels (Ca(v)3.2) in major pelvic ganglion neurons.	2002 Jun	12037187
The role of T-type calcium channels in morphine analgesia, development of antinociceptive tolerance and dependence to morphine, and morphine abstinence syndrome.	2002 Jun 28	12072160
Pharmacological interactions of statins.	2002 May	12044584
Calcium channel blockade limits transcriptional, translational and functional up-regulation of the cardiac calpain system after myocardial infarction.	2002 Oct 18	12393065
TGFbeta1 signaling via alphaVbeta6 integrin.	2003 Aug 7	12935295
Cellular mechanism for mibefradil-induced vasodilation of renal microcirculation: studies in the isolated perfused hydronephrotic kidney.	2003 Dec	14639089
The sources and sequestration of Ca(2+) contributing to neuroeffector Ca(2+) transients in the mouse vas deferens.	2003 Dec 1	14500773
A T-type calcium channel required for normal function of a mammalian mechanoreceptor.	2003 Jul	12808460
Detection of proarrhythmia in the female rabbit heart: blinded validation.	2003 Mar	12716112
Mechanism of active repolarization of inhibitory junction potential in murine colon.	2003 Nov	14561587
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	14612892
Effect of mibefradil on CYP3A4 in vivo.	2003 Oct	14517191
Reversal of experimental neuropathic pain by T-type calcium channel blockers.	2003 Sep	14499432

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%.

Name

Type

Language

MIBEFRADIL

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