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Details

Stereochemistry ACHIRAL
Molecular Formula C22H26N2O4S.C4H4O4
Molecular Weight 530.5921
Optical Activity UNSPECIFIED
Defined Stereocenters 2 / 2
E/Z Centers 1
Charge 0

SHOW SMILES / InChI
Structure of DILTIAZEM MALEATE

SMILES

CC(=O)O[C@]1([H])[C@]([H])(c2ccc(cc2)OC)Sc3ccccc3N(CCN(C)C)C1=O.C(\[H])(=C(\[H])/C(=O)O)/C(=O)O

InChI

InChIKey=WHBXLOWLFLTDMD-WECFPGDBSA-N
InChI=1S/C22H26N2O4S.C4H4O4/c1-15(25)28-20-21(16-9-11-17(27-4)12-10-16)29-19-8-6-5-7-18(19)24(22(20)26)14-13-23(2)3;5-3(6)1-2-4(7)8/h5-12,20-21H,13-14H2,1-4H3;1-2H,(H,5,6)(H,7,8)/b;2-1-/t20-,21+;/m1./s1

HIDE SMILES / InChI

Molecular Formula C4H4O4
Molecular Weight 116.0723
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 1
Optical Activity NONE

Molecular Formula C22H26N2O4S
Molecular Weight 414.5198
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 2 / 2
E/Z Centers 0
Optical Activity UNSPECIFIED

Diltiazem is a nondihydropyridines calcium channel blocker used in the treatment of hypertension, angina pectoris, and some types of arrhythmia. Diltiazem produces its antihypertensive effect primarily by relaxation of vascular smooth muscle and the resultant decrease in peripheral vascular resistance.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
21.0 nM [Ki]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
CARDIZEM

Approved Use

Diltiazem produces its antihypertensive effect primarily by relaxation of vascular smooth muscle and the resultant decrease in peripheral vascular resistance. The magnitude of blood pressure reduction is related to the degree of hypertension; thus hypertensive individuals experience an antihypertensive effect, whereas there is only a modest fall in blood pressure in normotensives.

Launch Date

4.05302411E11
Primary
CARDIZEM

Approved Use

Diltiazem has been shown to produce increases in exercise tolerance, probably due to its ability to reduce myocardial oxygen demand. This is accomplished via reductions in heart rate and systemic blood pressure at submaximal and maximal work loads. Diltiazem has been shown to be a potent dilator of coronary arteries, both epicardial and subendocardial. Spontaneous and ergonovine-induced coronary artery spasm are inhibited by diltiazem.

Launch Date

4.05302411E11
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
166.4 ng/mL
240 mg 1 times / day steady-state, oral
dose: 240 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
DILTIAZEM plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
2410 ng × h/mL
240 mg 1 times / day steady-state, oral
dose: 240 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
DILTIAZEM plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
7.5 h
360 mg single, oral
dose: 360 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
DILTIAZEM plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: FASTED
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
25%
360 mg single, oral
dose: 360 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
DILTIAZEM plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: FASTED
Overview

OverviewOther

Other InhibitorOther SubstrateOther Inducer






Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
weak
yes [IC50 0.6 uM]
yes [IC50 11 uM]
yes [IC50 120 uM]
yes (co-administration study)
Comment: Diltiazem is an inhibitor of CYP3A4 and has been shown to increase significantly the AUC of some statins.
yes [Ki 117 uM]
yes [Ki 12.5 uM]
yes [Ki 77.7 uM]
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
major
no
no (pharmacogenomic study)
Comment: results suggest that CYP3A5*3 has only a minor effect on the pharmacokinetics and metabolism of diltiazem
yes
yes
yes
weak (pharmacogenomic study)
Comment: Two of the most frequent alleles, CYP3A5 3 and CYP2D6 10, among Chinese do not have major impacts on the disposition of diltiazem and N-desmethyl diltiazem. However, the desacetyl diltiazem showed 2-fold accumulation in individuals with CYP2D6 10/10 genotype
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Antihypertensive efficacy and tolerability of once-daily sustained-release diltiazem alone and in combination with ramipril in hypertension.
1999 Oct
Influence of diltiazem on the pharmacokinetics of amlodipine in elderly hypertensive patients.
2001 Apr
[Unexpected formation of spiro(benzofuran-2,2'-(1,4)benzothiazines) from aurones].
2001 Apr
Atrial fibrillation: is rate stabilization a valid clinical strategy?
2001 Apr
Ionic mechanisms of aglycemic axon injury in mammalian central white matter.
2001 Apr
Slowing the progression of renal disease in diabetic patients.
2001 Apr
Voltage-dependent calcium channels in the rat retina: involvement in NMDA-stimulated influx of calcium.
2001 Apr
Contribution of amiloride-insensitive pathways to alveolar fluid clearance in adult rats.
2001 Apr
Atrial fibrillation control and cardioversion.
2001 Apr 7
Hexarelin, but not growth hormone, protects heart from damage induced in vitro by calcium deprivation replenishment.
2001 Feb
A case of lichenoid purpura possibly caused by diltiazem hydrochloride.
2001 Feb
The protective effects of high dose ascorbic acid and diltiazem on myocardial ischaemia-reperfusion injury.
2001 Feb
Efficacy and safety of out-of-hospital self-administered single-dose oral drug treatment in the management of infrequent, well-tolerated paroxysmal supraventricular tachycardia.
2001 Feb
Diltiazem-associated photodistributed hyperpigmentation: a review of 4 cases.
2001 Feb
L-type calcium channel blockers and EGTA enhance superoxide production in cardiac fibroblasts.
2001 Feb
Axonal L-type Ca2+ channels and anoxic injury in rat CNS white matter.
2001 Feb
Calcium antagonists as inhibitors of in vitro low density lipoprotein oxidation and glycation.
2001 Feb 1
Calcium channel blocker D-cis-diltiazem does not slow retinal degeneration in the PDE6B mutant rcd1 canine model of retinitis pigmentosa.
2001 Feb 25
Pharmacological interventions of cyanide-induced cytotoxicity and DNA damage in isolated rat thymocytes and their protective efficacy in vivo.
2001 Feb 3
Diltiazem downregulates IL-12 production by human dendritic cells.
2001 Feb-Mar
Diltiazem affects human dendritic cell maturation.
2001 Feb-Mar
Muscarinic activation of transient inward current and contraction in canine colon circular smooth muscle cells.
2001 Jan
Heart rate-lowering and -regulating effects of once-daily sustained-release diltiazem.
2001 Jan
Rho-kinase inhibitors prevent agonist-induced vasospasm in human internal mammary artery.
2001 Jan
Prehospital management of rapid atrial fibrillation: recommendations for treatment protocols.
2001 Jan
An in vitro investigation of the suitability of press-coated tablets with hydroxypropylmethylcellulose acetate succinate (HPMCAS) and hydrophobic additives in the outer shell for colon targeting.
2001 Jan 29
Protein kinase C activates store-operated Ca(2+) channels in human glomerular mesangial cells.
2001 Jul 13
Na+ effects on mitochondrial respiration and oxidative phosphorylation in diabetic hearts.
2001 Jun
Amiodarone versus diltiazem for rate control in critically ill patients with atrial tachyarrhythmias.
2001 Jun
Photostability and phototoxicity studies on diltiazem.
2001 Jun
Adsorptive stripping voltammetric determination of antihypertensive agent: diltiazem.
2001 Jun
Smooth muscle relaxation and local hydraulic impedance properties of the aorta.
2001 Jun
Calcium signaling pathways utilized by P2X receptors in freshly isolated preglomerular MVSMC.
2001 Jun
An alternative method to the evaluation of similarity factor in dissolution testing.
2001 Jun 4
Effect of simvastatin on vascular smooth muscle responsiveness: involvement of Ca(2+) homeostasis.
2001 Mar
Positive and negative contractile effects of somatostatin-14 on rat ventricular cardiomyocytes.
2001 Mar
Effect of angiotensin II on venodilator response to nitroglycerin.
2001 Mar
Effect of magnesium stearate or calcium stearate as additives on dissolution profiles of diltiazem hydrochloride from press-coated tablets with hydroxypropylmethylcellulose acetate succinate in the outer shell.
2001 Mar 23
Inhibition by nifedipine of adherence- and activated macrophage-induced death of human gingival fibroblasts.
2001 Mar 9
Heart rate-lowering calcium antagonists in hypertensive post-myocardial infarction patients.
2001 May
Trimetazidine for stable angina pectoris.
2001 May
Calcium-dependent effects of melatonin inhibition of glutamatergic response in rat striatum.
2001 May
The effects of diltiazem on hemodynamics and seizure duration during electroconvulsive therapy.
2001 May
[Attempted suicide with sustained release diltiazem].
2001 May 12
Study of processing parameters influencing the properties of diltiazem hydrochloride microspheres.
2001 May-Jun
Patents

Sample Use Guides

In Vivo Use Guide
When used as monotherapy, reasonable starting doses are 180 to 240 mg once daily, although some patients may respond to lower doses. Maximum antihypertensive effect is usually observed by 14 days of chronic therapy; therefore, dosage adjustments should be scheduled accordingly. The usual dosage range studied in clinical trials was 240 to 360 mg once daily. Individual patients may respond to higher doses of up to 480 mg once daily. Dosages for the treatment of angina should be adjusted to each patient's needs, starting with a dose of 120 or 180 mg once daily. Individual patients may respond to higher doses of up to 480 mg once daily. When necessary, titration may be carried out over a 7- to 14-day period.
Route of Administration: Oral
In Vitro Use Guide
Tissue homogenate of cerebral cortext and heart containing calcium channel receptors was used in a radioligand-binding assays. Cerebral cortices of male SD rats were homogenized. Hearts were also removed, perfused through aorta with ice-cold saline solution, and homogenized. Subsequently, the cardiac homogenates were filtered through four layers of cloth. Both cortical and cardiac homogenates were washed 5 times by centrifugation for 10 min at 48000 g. The final pelle was resuspended to a conc. of 50 mg of original wet tissue wt/mL of buffer and stored at -70°C. Tissue homogenate (200 uL) was incubated for 90 min in a dark room at 0°C with 100 uL of [3H]nitreddipine (3x10^-10M, 87 Ci/mmol) and 100 uL of the test compound dissolved in DMSO in 50 mM of Na-Hepes buffer, pH 7.4. The incubations were stopped by adding 4 mL of cold buffer followed by rapid filtratoin through glass fiber filter disks. The samples were subsequently washed 3 times with 4.5 mL of the same buffer and placed into scintill. vials. Diltiazem inhibited binding of [3H]nitrendipine with Ki of 21 nM.
Substance Class Chemical
Created
by admin
on Sat Jun 26 00:55:54 UTC 2021
Edited
by admin
on Sat Jun 26 00:55:54 UTC 2021
Record UNII
896626Q8XW
Record Status Validated (UNII)
Record Version
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Name Type Language
DILTIAZEM MALEATE
VANDF  
Common Name English
DILTIAZEM MALEATE [VANDF]
Common Name English
1,5-BENZOTHIAZEPIN-4(5H)-ONE, 3-(ACETYLOXY)-5-(2-(DIMETHYLAMINO)ETHYL)-2,3-DIHYDRO-2-(4-METHOXYPHENYL)-, (2S,3S)-, (2Z)-2-BUTENEDIOATE (1:1)
Systematic Name English
Code System Code Type Description
PUBCHEM
67938926
Created by admin on Sat Jun 26 00:55:54 UTC 2021 , Edited by admin on Sat Jun 26 00:55:54 UTC 2021
PRIMARY
CAS
139492-78-7
Created by admin on Sat Jun 26 00:55:54 UTC 2021 , Edited by admin on Sat Jun 26 00:55:54 UTC 2021
PRIMARY
DRUG BANK
DBSALT002322
Created by admin on Sat Jun 26 00:55:54 UTC 2021 , Edited by admin on Sat Jun 26 00:55:54 UTC 2021
PRIMARY
FDA UNII
896626Q8XW
Created by admin on Sat Jun 26 00:55:54 UTC 2021 , Edited by admin on Sat Jun 26 00:55:54 UTC 2021
PRIMARY
RXCUI
314592
Created by admin on Sat Jun 26 00:55:54 UTC 2021 , Edited by admin on Sat Jun 26 00:55:54 UTC 2021
PRIMARY RxNorm
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