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=C(OC)C=C(CCN(C)CCCC(C#N)(C(C)C)C2=CC(OC)=C(OC)C=C2)C=C1

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

Molecular Formula	C27H38N2O4
Molecular Weight	454.6016
Charge	0
Count

Stereochemistry	RACEMIC
Additional Stereochemistry	No
Defined Stereocenters	0 / 1
E/Z Centers	0
Optical Activity	( + / - )

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 91 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 8146		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 8146

Conditions

Condition	Modality	Highest Phase	Product
Angina 15 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018925s008lbl.pdf	Primary	Approved 8307	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 3.66336016E11
Arrhythmia 37 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018925s008lbl.pdf	Primary	Approved 8307	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 3.66336016E11
Essential hypertension 17 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018925s008lbl.pdf	Primary	Approved 8307	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 3.66336016E11

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 1670 inhibitor 1532	substrate 985 inhibitor 1695	inhibitor 1789	inhibitor 1570

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OCT1 498	CYP1A2 1013 CYP2C8 670 CYP2C18 138

Drug as perpetrator

Target	Modality	Activity
CYP2D6 1826	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/11996015/ Page: 146.0	likely
CYP3A4 1857	inhibitor 3185 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 1747	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/11996015/ Page: 99.0	weak
OCT1 513	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/19833842/	yes [IC50 1.23 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP1A2 1013	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/019152s044lbl.pdf#page=7 Page: 7.0	yes
CYP2C18 138	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/019152s044lbl.pdf#page=7 Page: 7.0	yes
CYP2C8 670	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/019152s044lbl.pdf#page=7 Page: 7.0	yes
CYP2C9 985	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/019152s044lbl.pdf#page=7 Page: 7.0	yes
CYP3A4 1670	substrate 3264 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 1603	inhibitor 1584 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
AHH Chemical co.,ltd	API-1634	http://www.ahhchemical.com/product/API-1634.html
Achemtek	0104-013440	http://www.achemtek.com/52-53-9
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
CSNpharm	CSN25647	https://www.csnpharm.com/products/verapamil.html
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
DC Chemicals	DC7880	http://www.dcchemicals.com/product_show-CP_16533_1_Verapamil_.html
Finetech	FT-0675801	http://www.finetechnology-ind.com/prod/detail/pub/36622-29-4.html
Finetech	FT-0603225	http://www.finetechnology-ind.com/prod/detail/pub/52-53-9.html
Hairui	HR137435	http://www.hairuichem.com/en/product/52-53-9.html
Lab Network	LN01346584	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01346584
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
eNovation Chemicals	K22170	https://www.enovationchem.com/ProductDetails.asp?ProductID=K22170
iChemical	EBD29756	http://www.ichemical.com/chemicals/cas-52-53-9
mcule	MCULE-3016077278	https://mcule.com/MCULE-3016077278/

PubMed

Title	Date	PubMed
[Asystole followed by cardiogenic shock after intravenous injection of verapamil].	1975 Mar-Apr	1094900
Rhabdomyolysis and acute renal failure in a cardiac transplant recipient due to multiple drug interactions.	2000 Dec	11149552
Motor and electrographic response of refractory experimental status epilepticus in rats and effect of calcium channel blockers.	2000 Feb	11218825
Transition-state formation in ATPase-negative mutants of human MDR1 protein.	2000 Oct 5	11027628
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
Refractory no-reflow successfully treated with local infusion of high-dose adenosine and verapamil--a case report.	2001 Feb	11228087
Selective drug resistant human osteosarcoma cell lines.	2001 Feb	11210963
Model organisms: new insights into ion channel and transporter function. L-type calcium channels regulate epithelial fluid transport in Drosophila melanogaster.	2001 Feb	11208535
Idiopathic sustained left ventricular tachycardia in pediatric patients.	2001 Feb	11207998
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
Kinetic profiling of P-glycoprotein-mediated drug efflux in rat and human intestinal epithelia.	2001 Feb	11160647
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
The stimulation of MAP kinase by 1,25(OH)(2)-vitamin D(3) in skeletal muscle cells is mediated by protein kinase C and calcium.	2001 Feb 28	11223176
Involvement of cyclic GMP in nitric-oxide-induced gastric relaxation Comparison of the actions of cyclic GMP and cyclic AMP.	2001 Jan	11218234
Volume-weighted mean nuclear volume and numerical nuclear density in the cardiomyocyte following enalapril and verapamil treatment.	2001 Jan	11213841
Identification of an organic anion transport system in the human colon carcinoma cell line HT29 clone 19A.	2001 Jan	11212217
The effects of vasopressin in isolated rat hearts.	2001 Jan	11211571
Penetration of verapamil hydrochloride in the presence of sodium glycocholate as penetration enhancer through mucous membrane.	2001 Jan	11210675
A new chronotherapeutic oral drug absorption system for verapamil optimizes blood pressure control in the morning.	2001 Jan	11206672
Verapamil prevents stretch-induced shortening of atrial effective refractory period in langendorff-perfused rabbit heart.	2001 Jan	11204090
Effects of simultaneous atrioventricular pacing on atrial refractoriness and atrial fibrillation inducibility: role of atrial mechanoelectrical feedback.	2001 Jan	11204083
Transport of [3H]MPP+ in an immortalized rat brain microvessel endothelial cell line (RBE 4).	2001 Jan	11191826
Ionized magnesium in the homeostasis of cells: intracellular threshold for Mg(2+) in human platelets.	2001 Jan	11163035
Prevention of cardiomyopathy in mouse models lacking the smooth muscle sarcoglycan-sarcospan complex.	2001 Jan	11160141
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
Prognostic implications of intima-media thickness and plaques in the carotid and femoral arteries in patients with stable angina pectoris.	2001 Jan	11133211
Calcium channel antagonists enhance retention of passive avoidance and maze learning in mice.	2001 Jan	11124048
A novel zidovudine uptake system in microglia.	2001 Jan	11123374
Hepatic uptake of synthetic chlorogenic acid derivatives by the organic anion transport proteins.	2001 Jan	11123367
Evaluation of a vincristine resistant Caco-2 cell line for use in a calcein AM extrusion screening assay for P-glycoprotein interaction.	2001 Jan	11113639
Role of stimulatory guanine nucleotide binding protein (GSalpha) in proliferation of PC-3M prostate cancer cells.	2001 Jan 1	11149419
Verapamil block of large-conductance Ca-activated K channels in rat aortic myocytes.	2001 Jan 15	11220361
In vitro and in vivo reversal of P-glycoprotein-mediated multidrug resistance by a novel potent modulator, XR9576.	2001 Jan 15	11212278
Behavioural and anti-psychotic effects of Ca2+ channel blockers in rhesus monkey.	2001 Jan 26	11165225
Effect of intraovarian factors on porcine follicular cells: cumulus expansion, granulosa and cumulus cell progesterone production.	2001 Jan 31	11182513
The effects of LY393613, nimodipine and verapamil, in focal cerebral ischaemia.	2001 Jan 5	11137861
Cardiogenic shock following a single therapeutic oral dose of verapamil.	2001 Jan-Feb	11219325
Verapamil SR and trandolapril combination therapy is safe and effective in hypertensive patients with metabolic disorders.	2001 Jan-Feb	11219319
Requirement of neural activity for the maintenance of dopaminergic neurons in rat midbrain slice cultures.	2001 Mar 16	11226637
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
How to manage atrial fibrillation: an update on recent clinical trials.	2001 Mar-Apr	11209144

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.

Substance Class	Chemical Created by `admin` on `Sun Dec 18 20:43:16 UTC 2022` Edited by `admin` on `Sun Dec 18 20:43:16 UTC 2022`
Record UNII	CJ0O37KU29
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

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

CP-16,533-1

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