DEXVERAPAMIL HYDROCHLORIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C27H38N2O4.ClH
Molecular Weight	491.063
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cl.COC1=C(OC)C=C(CCN(C)CCC[C@@](C#N)(C(C)C)C2=CC(OC)=C(OC)C=C2)C=C1

InChI

InChIKey=DOQPXTMNIUCOSY-HZPIKELBSA-N

InChI=1S/C27H38N2O4.ClH/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;1H/t27-;/m1./s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/17646169 | http://www.google.ch/patents/US5889060http://adisinsight.springer.com/drugs/800007413
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/17646169 | http://adisinsight.springer.com/drugs/800022706 | http://www.drugdevelopment-technology.com/projects/rezular/

Dexverapamil (R-verapamil) is an enantiomer of verapamil. R-isomer behaved as an inhibitor of multidrug-resistant protein MRP1 (involved in the cancer cell multidrug resistance phenotype). It was developed by Knoll (BASF Pharma) as a chemosensitiser and/or modulator of multidrug resistance for use in combination with cancer chemotherapy. Dexverapamil was undergoing phase II clinical studies in France, Italy, Spain, United Kingdom and the US in patients with various cancers. It was also undergoing phase I clinical trials in Japan where it was licensed to Mitsui and Mitsui Toatsu Chemicals. However, development was discontinued. Dexverapamil (R-verapamil) has been developing by AGI therapeutics for the treatment of Irritable bowel syndrome however development was discontinued.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Multidrug resistance protein 1 8 Target ID: P08183 Gene ID: 5243.0 Gene Symbol: ABCB1 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/17646169	Inhibitor 8297
Multidrug resistance-associated protein 1 15 Target ID: CHEMBL3004 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17646169	Inhibitor 8297

Conditions

Condition	Modality	Highest Phase	Product
Irritable bowel syndrome 60 Sources: http://adisinsight.springer.com/drugs/800022706	Primary	Phase III 656	REZULAR Approved Use Unknown
Cluster headache 10 Sources: https://clinicaltrials.gov/ct2/show/NCT02209155	Preventing	Phase II 1132	Unknown Approved Use Unknown
Cancer 592 Sources: http://adisinsight.springer.com/drugs/800007413	Primary	Phase II 1132	Unknown Approved Use Unknown
Angina 32 Sources: http://www.google.ch/patents/US5889060	Primary	Not Provided 504	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
2103 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8398588/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	DEXVERAPAMIL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
308 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8398588/	250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered:	DEXVERAPAMIL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
892 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8398588/	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	DEXVERAPAMIL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
11818 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8398588/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	DEXVERAPAMIL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1707 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8398588/	250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered:	DEXVERAPAMIL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
3974 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8398588/	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	DEXVERAPAMIL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
5.5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8398588/	1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered:	DEXVERAPAMIL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
5.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8398588/	250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered:	DEXVERAPAMIL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8398588/	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	DEXVERAPAMIL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

PubMed

Title	Date	PubMed
Chrono: a community-based hypertension trial of a chronotherapeutic formulation of verapamil.	2002 Nov-Dec	12424503
Actions of R- and S-verapamil and nifedipine on rat vascular and intestinal smooth muscle.	2004 Jul	15541013
Pharmacodynamics of controlled release verapamil in patients with hypertension: an analysis using spline functions.	2004 Jul	15248191
Nonstructural carbohydrate supplementation of yearling heifers and range beef cows.	2004 Sep	15446489
[Endothelium of myocardium microvessel under conditions of hypothermia, ischemia, reperfusion and pharmaco-cold cardioplegia with calcium antagonist].	2005	16602237
[Efficacy of and tolerance to combined therapy with dihydropyridine and non-dihydropyridine Ca antagonists in patients with moderate arterial hypertension].	2005	16117423
Effect of early phase adjuvant arthritis on hepatic P450 enzymes and pharmacokinetics of verapamil: an alternative approach to the use of an animal model of inflammation for pharmacokinetic studies.	2005 Apr	15659540
Development and characterization of an immobilized human organic cation transporter based liquid chromatographic stationary phase.	2005 Apr 25	15734168
Littoral cell angioma of the spleen treated by laparoscopic splenectomy.	2005 Apr-Jun	15984716
Phosphorus-doped and undoped glassy carbon indicator electrodes in controlled-current potentiometric titrations of bromide- or chloride-containing active ingredients in some pharmaceutical preparations.	2005 Feb 23	15708666
Efficacy of using a combination of rendered protein products as an undegradable intake protein supplement for lactating, winter-calving, beef cows fed bromegrass hay.	2005 Jan	15583059
Effects of rhubarb on isolated gastric muscle strips of guinea pigs.	2005 May 7	15849832
Multidrug resistance: retrospect and prospects in anti-cancer drug treatment.	2006	16842198
Cardiovascular effects of (R)- and (S)-verapamil and racemic verapamil in humans: a placebo-controlled study.	2006 Aug	16823584
The effect of short- and long-term administration of verapamil on the disposition of cytochrome P450 3A and P-glycoprotein substrates.	2006 Mar	16513446
Cell death-mediated antiviral effect of chitosan in tobacco.	2006 Nov-Dec	17097297
The effect of gender on the pharmacokinetics of verapamil and norverapamil in human.	2006 Oct	16892180
Corn oil supplementation to steers grazing endophyte-free tall fescue. I. Effects on in vivo digestibility, performance, and carcass traits.	2007 May	17224464
Cytochrome P450 3A5 genotype is associated with verapamil response in healthy subjects.	2007 Nov	17443134
[A 48-year-old woman's survival from a massive verapamil overdose].	2007 Nov 19	18078664
Effects of restricted feeding of beef heifers during the postweaning period on growth, efficiency, and ultrasound carcass characteristics.	2007 Oct	17565051
(R)- and (S)-verapamil differentially modulate the multidrug-resistant protein MRP1.	2007 Oct 26	17646169
Manure nutrient excretion by lactating cows fed exogenous phytase and cellulase.	2007 Sep	17699056
Pancreatic mass, cellularity, and alpha-amylase and trypsin activity in feedlot steers fed diets differing in crude protein concentration.	2008 Apr	18192547
Studies of verapamil binding to human serum albumin by high-performance affinity chromatography.	2008 Dec 1	18980867
Efficacy of AZM therapy in patients with gingival overgrowth induced by Cyclosporine A: a systematic review.	2008 Dec 16	19087331
Strategies for enhanced drug delivery to the central nervous system.	2008 Mar-Apr	20046703
Effects of divergent selection for serum insulin-like growth factor-I concentration on performance, feed efficiency, and ultrasound measures of carcass composition traits in Angus bulls and heifers.	2008 Nov	18676718
Corn oil or corn grain supplementation to steers grazing endophyte-free tall fescue. I. Effects on in vivo digestibility, performance, and carcass quality.	2008 Nov	18539823
Exploring enantiospecific ligand-protein interactions using cellular membrane affinity chromatography: chiral recognition as a dynamic process.	2008 Nov 1	18723411
High-Resolution Images with Minimum Energy Dissipation and Maximum Field-of-View in Camera-Based Wireless Multimedia Sensor Networks.	2009	22454591
Role of multidrug transporters in neurotherapeutics.	2009 Apr	20142853
Pretreatment with R(+)-verapamil significantly reduces mortality and cytokine expression in murine model of septic shock.	2009 Apr	19291858
Effect of calcium-regulating hormones and calcium channel modulators on glucose consumption by muscle and adipose tissues in vivo and in vitro.	2009 Aug	20027320
Determinants of quality of life of youths in an English-speaking Caribbean nation.	2009 Dec	22666725
Phenotypic and genetic relationships of residual feed intake with performance and ultrasound carcass traits in Brangus heifers.	2009 Dec	19717782
The effect of infliximab on hepatic cytochrome P450 and pharmacokinetics of verapamil in rats with pre-adjuvant arthritis: a drug-disease and drug-drug interaction.	2009 Jul	19371259
Different effects of ketoconazole on the stereoselective first-pass metabolism of R/S-verapamil in the intestine and the liver: important for the mechanistic understanding of first-pass drug-drug interactions.	2009 Nov	19687151
Focus on adoptive T cell transfer trials in melanoma.	2010	21234353
Impact of reduced marker set estimation of genomic relationship matrices on genomic selection for feed efficiency in Angus cattle.	2010 Apr 19	20403185
(E)-4-Bromo-N-(2,3-dimeth-oxy-benzyl-idene)aniline.	2010 Aug 4	21588588
Metabolic activity and mRNA levels of human cardiac CYP450s involved in drug metabolism.	2010 Dec 14	21179487
Unresolved abdominal mass in an adult cryptorchid testis: a case report.	2010 Dec 7	21189838
(E)-4-Bromo-N-(2,3,4-trimeth-oxy-benzyl-idene)aniline.	2010 Jul 21	21588366
The synthesis and characterization of cellular membrane affinity chromatography columns for the study of human multidrug resistant proteins MRP1, MRP2 and human breast cancer resistant protein BCRP using membranes obtained from Spodoptera frugiperda (Sf9) insect cells.	2010 Jun 15	20441926
Development of 2D chiral chromatography with accelerator mass spectrometry for quantification of (14)C-labeled R- and S-verapamil in plasma.	2010 Mar	21083250
Pigeon peas as a supplement for lactating dairy cows fed corn silage-based diets.	2010 Nov	20965347
Effect of feeding alfalfa hay or Tifton 85 bermudagrass haylage with or without a cellulase enzyme on performance of Holstein cows.	2010 Nov	20965344
Assessment of pulmonary function and serum substance levels in newborn and juvenile rats.	2010 Nov	20493942
Hypertension, antihypertensive medication use, and breast cancer risk in the California Teachers Study cohort.	2010 Oct	20526803

Patents

Sample Use Guides

In Vivo Use Guide

Administration of (R)-verapamil may be by any of the conventional routes, for instance oral, intravenous, sublingual, topical and rectal. Conventional formulations may verapamil will be formulated for oral administration. Typically, a suitable dosage of the active component is up to 500 mg per day, but any of the standard dosages for the racemate may be used.

Route of Administration: Other

In Vitro Use Guide

It was investigated the individual effects of each enantiomer by comparison with the racemic mixture. The cellular effects were tested on both control and human MRP1 cDNA-transfected baby hamster kidney 21 (BHK-21) cells (MRP1-BHK-21). Racemic verapamil was cytotoxic for MRP1-BHK-21 cells at concentrations <10-20 μM, which were ineffective in control BHK-21 cells. The R- and S-enantiomers were highly discriminated because (R)-verapamil did not exhibit any cytotoxicity for the two types of cell, whereas (S)-verapamil displayed a killing activity, even more potent than that observed with the racemic mixture at the same concentration.

Name

Type

Language

DEXVERAPAMIL HYDROCHLORIDE

Common Name

English

(+)-VERAPAMIL HYDROCHLORIDE

Common Name

English

VERAPAMIL HYDROCHLORIDE, (+)-

Common Name

English

LU-33925

Code

English

BENZENEACETONITRILE, .ALPHA.-(3-((2-(3,4-DIMETHOXYPHENYL)ETHYL)METHYLAMINO)PROPYL)-3,4-DIMETHOXY-.ALPHA.-(1-METHYLETHYL)-, MONOHYDROCHLORIDE, (R)-

Common Name

English

(R)-VERAPAMIL HYDROCHLORIDE

Common Name

English

BENZENEACETONITRILE, .ALPHA.-(3-((2-(3,4-DIMETHOXYPHENYL)ETHYL)METHYLAMINO)PROPYL)-3,4-DIMETHOXY-.ALPHA.-(1-METHYLETHYL)-, MONOHYDROCHLORIDE, (.ALPHA.R)-

Common Name

English

VERAPAMIL (R)-FORM HYDROCHLORIDE [MI]

Common Name

English

NSC-632821

Code

English

DEXVERAPAMIL MONOHYDROCHLORIDE

Common Name

English

Code System Code Type Description

FDA UNII

B0P742MK5O