VERAPAMIL

First approved in 1978

Details

Stereochemistry	RACEMIC
Molecular Formula	C27H38N2O4
Molecular Weight	454.6016
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

COC1=CC=C(CCN(C)CCCC(C#N)(C(C)C)C2=CC=C(OC)C(OC)=C2)C=C1OC

InChI

InChIKey=SGTNSNPWRIOYBX-UHFFFAOYSA-N

InChI=1S/C27H38N2O4/c1-20(2)27(19-28,22-10-12-24(31-5)26(18-22)33-7)14-8-15-29(3)16-13-21-9-11-23(30-4)25(17-21)32-6/h9-12,17-18,20H,8,13-16H2,1-7H3

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018817s032lbl.pdf
Curator's Comment: Description was created based on several sources, including https://www.drugbank.ca/drugs/DB00661

Verapamil is a FDA approved drug used to treat high blood pressure and to control chest pain. Verapamil is an L-type calcium channel blocker that also has antiarrythmic activity. The R-enantiomer is more effective at reducing blood pressure compared to the S-enantiomer. However, the S-enantiomer is 20 times more potent than the R-enantiomer at prolonging the PR interval in treating arrhythmias. Verapamil inhibits voltage-dependent calcium channels. Specifically, its effect on L-type calcium channels in the heart causes a reduction in ionotropy and chronotropy, thuis reducing heart rate and blood pressure. Verapamil's mechanism of effect in cluster headache is thought to be linked to its calcium-channel blocker effect, but which channel subtypes are involved is presently not known.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Voltage-gated L-type calcium channel 95 Target ID: CHEMBL2095229 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018817s027lbl.pdf \| https://www.ncbi.nlm.nih.gov/pubmed/27856310 \| https://www.ncbi.nlm.nih.gov/pubmed/19125880	Inhibitor 8504		3.4 µM [IC50]
Voltage-gated L-type calcium channel alpha-1C subunit 44 Target ID: CHEMBL1940 Sources: https://www.drugbank.ca/drugs/DB00661 \| https://www.ncbi.nlm.nih.gov/pubmed/15880143	Inhibitor 8504

Conditions

Condition	Modality	Highest Phase	Product
Angina 34 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018925s008lbl.pdf	Primary	Approved 8583	CALAN Approved Use CALAN tablets are indicated for the treatment of the following: Angina 1. Angina at rest including: — Vasospastic (Prinzmetal’s variant) angina — Unstable (crescendo, pre-infarction) angina 2. Chronic stable angina (classic effort-associated angina) Arrhythmias 1. In association with digitalis for the control of ventricular rate at rest and during stress in patients with chronic atrial flutter and/or atrial fibrillation (see WARNINGS: Accessory bypass tract) 2. Prophylaxis of repetitive paroxysmal supraventricular tachycardia Essential hypertension CALAN is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug. Launch Date 1981
Arrhythmia 45 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018925s008lbl.pdf	Primary	Approved 8583	CALAN Approved Use CALAN tablets are indicated for the treatment of the following: Angina 1. Angina at rest including: — Vasospastic (Prinzmetal’s variant) angina — Unstable (crescendo, pre-infarction) angina 2. Chronic stable angina (classic effort-associated angina) Arrhythmias 1. In association with digitalis for the control of ventricular rate at rest and during stress in patients with chronic atrial flutter and/or atrial fibrillation (see WARNINGS: Accessory bypass tract) 2. Prophylaxis of repetitive paroxysmal supraventricular tachycardia Essential hypertension CALAN is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug. Launch Date 1981
Essential hypertension 17 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018925s008lbl.pdf	Primary	Approved 8583	CALAN Approved Use CALAN tablets are indicated for the treatment of the following: Angina 1. Angina at rest including: — Vasospastic (Prinzmetal’s variant) angina — Unstable (crescendo, pre-infarction) angina 2. Chronic stable angina (classic effort-associated angina) Arrhythmias 1. In association with digitalis for the control of ventricular rate at rest and during stress in patients with chronic atrial flutter and/or atrial fibrillation (see WARNINGS: Accessory bypass tract) 2. Prophylaxis of repetitive paroxysmal supraventricular tachycardia Essential hypertension CALAN is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug. Launch Date 1981

C_max

Value	Dose	Co-administered	Analyte	Population
139.28 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16892180	80 mg single, oral dose: 80 mg route of administration: Oral experiment type: SINGLE co-administered:		VERAPAMIL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
367.05 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16892180	80 mg single, oral dose: 80 mg route of administration: Oral experiment type: SINGLE co-administered:		VERAPAMIL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
7.15 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16892180	80 mg single, oral dose: 80 mg route of administration: Oral experiment type: SINGLE co-administered:		VERAPAMIL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
9.9% EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/6209501			VERAPAMIL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946 inhibitor 2252	substrate 1193 inhibitor 2438	inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OCT1 620	CYP1A2 1197 CYP2C8 810 CYP2C18 149

Drug as perpetrator

Target	Modality	Activity
CYP2D6 2546	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/11996015/ Page: 146.0	likely
CYP3A4 2633	inhibitor 4027 Sources: https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1046/j.1365-2125.2001.01386.x#page=1 Page: 1.0	moderate [IC50 23 uM]
CYP2C9 2497	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/11996015/ Page: 99.0	weak
OCT1 656	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/19833842/	yes [IC50 1.23 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP1A2 1197	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/019152s044lbl.pdf#page=7 Page: 7.0	yes
CYP2C18 149	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/019152s044lbl.pdf#page=7 Page: 7.0	yes
CYP2C8 810	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/019152s044lbl.pdf#page=7 Page: 7.0	yes
CYP2C9 1193	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/019152s044lbl.pdf#page=7 Page: 7.0	yes
CYP3A4 1946	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/019152s044lbl.pdf#page=7 Page: 7.0	yes	yes (co-administration study) Comment: Co-administration of multiple doses of 10 mg of verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5-fold that following simvastatin alone; Clinically significant interactions have been reported with inhibitors of CYP3A4 (e.g., erythromycin, ritonavir) causing elevation of plasma levels of verapamil while inducers of CYP3A4 (e.g., rifampin) have caused a lowering of plasma levels of verapamil Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/019152s044lbl.pdf#page=7 Page: 7.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://pubmed.ncbi.nlm.nih.gov/10325236/

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY526351	https://www.001chemical.com/chem/152-11-4
001 Chemical	DY558136	https://www.001chemical.com/chem/52-53-9
3B Scientific (Wuhan) Corp	3B2-0664	http://www.3bsc.com/index/pro_info.php?id=20020
Achemtek	0104-013440	http://www.achemtek.com/52-53-9
AHH Chemical co.,ltd	API-1634	http://www.ahhchemical.com/product/API-1634.html
Alsachim	4116	http://www.alsachim.com/product-C5426-glo.bal-view.html
Ambeed	A149080	https://www.ambeed.com/products/52-53-9.html
AvaChem Scientific	4687B	http://www.avachem.com/productSearch.asp?4687B
Avantor Inc	101097-322	https://us.vwr.com/store/catalog/product.jsp?catalog_number=101097-322
BLD Pharm	BD156394	http://www.bldpharm.com/products/52-53-9.html
BroadPharm	BP-21223	http://www.broadpharm.com/web/product.php?catalog=BP-21223
Chem Scene	CS-0002967	http://www.chemscene.com/52-53-9.html
ChemMol	30105063	http://www.chemmol.com/chemmol/30105063.html
ChemMol	49417199	http://www.chemmol.com/chemmol/49417199.html
ChemMol	99097786	http://www.chemmol.com/chemmol/99097786.html
Chemspace	CSSB00000051941	https://chem-space.com/CSSB00000051941
Clearsynth	CS-O-30814	https://www.clearsynth.com/en/CSO30814.html
CSNpharm	CSN25647	https://www.csnpharm.com/products/verapamil.html
DC Chemicals	DC7880	http://www.dcchemicals.com/product_show-CP_16533_1_Verapamil_.html
eNovation Chemicals	K22170	https://www.enovationchem.com/ProductDetails.asp?ProductID=K22170
Finetech	FT-0603225	http://www.finetechnology-ind.com/prod/detail/pub/52-53-9.html
Finetech	FT-0675801	http://www.finetechnology-ind.com/prod/detail/pub/36622-29-4.html
Hairui	HR137435	http://www.hairuichem.com/en/product/52-53-9.html
iChemical	EBD29756	http://www.ichemical.com/chemicals/cas-52-53-9
Lab Network	LN01346584	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01346584
mcule	MCULE-3016077278	https://mcule.com/MCULE-3016077278/
MedChem Express	HY-14275	https://www.medchemexpress.com/verapamil.html
Molcore	MC526351	https://www.molcore.com/product/152-11-4
Molcore	MC558136	https://www.molcore.com/product/52-53-9
OChem	5898	http://www.ocheminc.com/index.php?act=psearch&pid=52V114
Parchem	18406	http://www.parchem.com/chemical-supplier-distributor/Linoleamidopropyl-PG-Dimonium-Chloride-Phosphate-008406.aspx
Parchem	30276	http://www.parchem.com/chemical-supplier-distributor/Verapamil-020276.aspx
Smolecule	S546686	http://www.smolecule.com/products/s546686
THE BioTek	bt-285978	https://www.thebiotek.com/product/inhibitors/bt-285978

PubMed

Title	Date	PubMed
[Mapping electrocardiographic fields in heart hypertrophy].	1998	10803286
[The importance of the ion-transport systems of the sarcolemma and sarcoplasmic reticulum in changing rat cardiac contractile function under a hypersodium medium].	1999 Apr	10513388
Evidence of sex related differences in the effects of calcium channel blockers on neuroleptic-induced catalepsy in mice.	1999 Feb	10368871
[Verapamil-responsive ventricular tachycardia in small children: a case report and review of the literature].	1999 Feb	10208059
Comparison of intravenous metoprolol, verapamil and diltiazem on the attenuation of haemodynamic changes associated with tracheal extubation.	1999 Jul	10457878
[Verapamil sensitive ventricular tachycardia with myocardial failure in a 2-year-old child].	1999 May	10413860
Intestinal secretion of intravenous talinolol is inhibited by luminal R-verapamil.	1999 Sep	10511059
Complete atrioventricular blockade secondary to conventional-release verapamil in a patient on hemodialysis.	1999 Sep	10461042
Motor and electrographic response of refractory experimental status epilepticus in rats and effect of calcium channel blockers.	2000 Feb	11218825
KCNA10: a novel ion channel functionally related to both voltage-gated potassium and CNG cation channels.	2000 Jun	10836990
Acute onset of auditory hallucinations after initiation of celecoxib therapy.	2000 Jun	10831492
Effect of metoprolol and verapamil administered separately and concurrently after single doses on liver blood flow and drug disposition.	2000 May	10806607
Activating transcription factor 2-derived peptides alter resistance of human tumor cell lines to ultraviolet irradiation and chemical treatment.	2001 Feb	11234888
[Treatment of cluster headache].	2001 Feb	11234673
Pretreatment with potent P-glycoprotein ligands may increase intestinal secretion in rats.	2001 Feb	11231107
Oxidized-LDL enhances coronary vasoconstriction by increasing the activity of protein kinase C isoforms alpha and epsilon.	2001 Feb	11230335
Selective drug resistant human osteosarcoma cell lines.	2001 Feb	11210963
A bioreversible prodrug approach designed to shift mechanism of brain uptake for amino-acid-containing anticancer agents.	2001 Feb	11181816
Inward calcium currents in cultured and freshly isolated detrusor muscle cells: evidence of a T-type calcium current.	2001 Feb	11176448
Dysfunction of polymorphonuclear leukocytes in uremia: role of parathyroid hormone.	2001 Feb	11169010
Pre- or post-ischemic treatment with a novel Na+/Ca2+ exchange inhibitor, KB-R7943, shows renal protective effects in rats with ischemic acute renal failure.	2001 Feb	11160625
Pharmacokinetic interaction of cytochrome P450 3A-related compounds with rhodamine 123, a P-glycoprotein substrate, in rats pretreated with dexamethasone.	2001 Feb	11159804
A flow cell assay for evaluation of whole cell drug efflux kinetics: analysis of paclitaxel efflux in CCRF-CEM leukemia cells overexpressing P-glycoprotein.	2001 Feb	11159798
Infusional CHOP chemotherapy (CVAD) with or without chemosensitizers offers no advantage over standard CHOP therapy in the treatment of lymphoma: a Southwest Oncology Group Study.	2001 Feb 1	11157027
Multidrug resistance protein (MRP) activity in normal mature leukocytes and CD34-positive hematopoietic cells from peripheral blood.	2001 Feb 2	11233999
Mechanisms of hydrogen peroxide-induced relaxation in rabbit mesenteric small artery.	2001 Feb 2	11166293
Cardiovascular action of a cardioselective Ca(2+)channel blocker AH-1058 in conscious dogs assessed by telemetry.	2001 Feb 9	11173068
Penetration of verapamil hydrochloride in the presence of sodium glycocholate as penetration enhancer through mucous membrane.	2001 Jan	11210675
Sarcoglycan, the heart, and skeletal muscles: new treatment, old drug?	2001 Jan	11160128
Modulator activity of PSC 833 and cyclosporin-A in vincristine and doxorubicin-selected multidrug resistant murine leukemic cells.	2001 Jan	11137565
P-glycoprotein-mediated drug secretion in mouse proximal tubule perfused in vitro.	2001 Jan	11134265
Competitive and allosteric interactions in ligand binding to P-glycoprotein as observed on an immobilized P-glycoprotein liquid chromatographic stationary phase.	2001 Jan	11125025
Calcium channel antagonists enhance retention of passive avoidance and maze learning in mice.	2001 Jan	11124048
Role of stimulatory guanine nucleotide binding protein (GSalpha) in proliferation of PC-3M prostate cancer cells.	2001 Jan 1	11149419
Suppression by verapamil of bombesin-enhanced peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane in wistar rats.	2001 Jan-Feb	11125235
Correlation between steady-state ATP hydrolysis and vanadate-induced ADP trapping in Human P-glycoprotein. Evidence for ADP release as the rate-limiting step in the catalytic cycle and its modulation by substrates.	2001 Mar 23	11121420
The effect of cardiac arrest on the blood-testis barrier to albumin, tumor necrosis factor-alpha, pituitary adenylate cyclase activating polypeptide, sucrose, and verapamil in the mouse.	2001 Mar-Apr	11229799

Patents

Sample Use Guides

In Vivo Use Guide

Angina: Clinical trials show that the usual dose is 80 mg to 120 mg three times a day. However, 40 mg three times a day may be warranted in patients who may have an increased response to verapamil (eg, decreased hepatic function, elderly, etc). Upward titration should be based on therapeutic efficacy and safety evaluated approximately eight hours after dosing. Dosage may be increased at daily (eg, patients with unstable angina) or weekly intervals until optimum clinical response is obtained. Arrhythmias: The dosage in digitalized patients with chronic atrial fibrillation (see PRECAUTIONS) ranges from 240 to 320 mg/day in divided (t.i.d. or q.i.d.) doses. The dosage for prophylaxis of PSVT (non-digitalized patients) ranges from 240 to 480 mg/day in divided (t.i.d. or q.i.d.) doses. In general, maximum effects for any given dosage will be apparent during the first 48 hours of therapy. Essential hypertension: Dose should be individualized by titration. The usual initial monotherapy dose in clinical trials was 80 mg three times a day (240 mg/day). Daily dosages of 360 and 480 mg have been used but there is no evidence that dosages beyond 360 mg provided added effect. Consideration should be given to beginning titration at 40 mg three times per day in patients who might respond to lower doses, such as the elderly or people of small stature. The antihypertensive effects of CALAN are evident within the first week of therapy. Upward titration should be based on therapeutic efficacy, assessed at the end of the dosing interval.

Route of Administration: Other

In Vitro Use Guide

Blockade of L-type calcium channels by verapamil (50 um) prevented a Norgestrel-induced calcium influx in stressed 661W photoreceptor-like cells.

Name

Type

Language

CP-16,533-1

Preferred Name

English

VERAPAMIL

Official Name

English

VERAPAMIL SLOW RELEASE

Common Name

English

VERAPAMIL [USAN]

Common Name

English

D-365

Code

English

Verapamil [WHO-DD]

Common Name

English

VERAPAMIL [VANDF]

Common Name

English

CP-165331

Code

English

verapamil [INN]

Common Name

English

VERAPAMIL [MI]

Common Name

English

(±)-5-((3,4-DIMETHOXYPHENETHYL)METHYLAMINO)-2-(3,4-DIMETHOXYPHENYL)-2-ISOPROPYLVALERONITRILE

Systematic Name

English

Classification Tree Code System Code

NDF-RT

N0000175566