Tmic
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Record Information
Version2.0
Creation Date2009-07-21 20:26:39 UTC
Update Date2014-12-24 20:25:51 UTC
Accession NumberT3D2758
Identification
Common NameDiltiazem
ClassSmall Molecule
DescriptionDiltiazem is only found in individuals that have used or taken this drug. It is a benzothiazepine derivative with vasodilating action due to its antagonism of the actions of the calcium ion in membrane functions. It is also teratogenic. Possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, diltiazem, like verapamil, inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. The resultant inhibition of the contractile processes of the myocardial smooth muscle cells leads to dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue.
Compound Type
  • Amide
  • Amine
  • Antihypertensive Agent
  • Calcium Channel Blocker
  • Cardiovascular Agent
  • Drug
  • Ester
  • Ether
  • Metabolite
  • Organic Compound
  • Synthetic Compound
  • Vasodilator Agent
Chemical Structure
Thumb
Synonyms
Synonym
(+)-cis-5-[2-(dimethylamino)Ethyl]-2,3-dihydro-3-hydroxy-2-(P-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one acetate ester
(2S,3S)-5-(2-(dimethylamino)Ethyl)-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl acetate
(2S-cis)-3-(Acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one
Acalix
Acetic acid (2S,3S)-5-(2-dimethylamino-ethyl)-2-(4-methoxy-phenyl)-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepin-3-yl ester
Adizem
Altiazem
Anoheal
Calcicard
Cardizem
Cartia
Cartia XT
D-cis-Diltiazem
Dilacor
Dilacor-XR
Dilcontin
Dilrene
DILT-CD
Diltia XT
Diltiazemum
Dilticard
DILTZAC
Dilzem
Herbesser
Incoril AP
Masdil
Surazem
TAZTIA
Tiazac
Viazem
Chemical FormulaC22H26N2O4S
Average Molecular Mass414.518 g/mol
Monoisotopic Mass414.161 g/mol
CAS Registry Number42399-41-7
IUPAC Name(2S,3S)-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate
Traditional Namediltiazem
SMILES[H][C@]1(OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S[C@@]1([H])C1=CC=C(OC)C=C1
InChI IdentifierInChI=1S/C22H26N2O4S/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/h5-12,20-21H,13-14H2,1-4H3/t20-,21+/m1/s1
InChI KeyInChIKey=HSUGRBWQSSZJOP-RTWAWAEBSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as benzothiazepines. These are organic compounds containing a benzene fused to a thiazepine ring (a seven-membered ring with a nitrogen atom and a sulfur atom replacing two carbon atoms).
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassBenzothiazepines
Sub ClassNot Available
Direct ParentBenzothiazepines
Alternative Parents
Substituents
  • Benzothiazepine
  • Phenoxy compound
  • Aryl thioether
  • Anisole
  • Phenol ether
  • Methoxybenzene
  • Alkyl aryl ether
  • Alkylarylthioether
  • Monocyclic benzene moiety
  • Benzenoid
  • Tertiary carboxylic acid amide
  • Amino acid or derivatives
  • Carboxamide group
  • Carboxylic acid ester
  • Lactam
  • Tertiary amine
  • Tertiary aliphatic amine
  • Monocarboxylic acid or derivatives
  • Ether
  • Carboxylic acid derivative
  • Azacycle
  • Thioether
  • Organonitrogen compound
  • Organic oxygen compound
  • Organic nitrogen compound
  • Amine
  • Carbonyl group
  • Organic oxide
  • Organooxygen compound
  • Hydrocarbon derivative
  • Organopnictogen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
  • 5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate (CHEBI:101278 )
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point187-188°C
Boiling PointNot Available
Solubility465 mg/L (at 25°C)
LogP2.8
Predicted Properties
PropertyValueSource
Water Solubility0.017 g/LALOGPS
logP3.09ALOGPS
logP2.73ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)12.86ChemAxon
pKa (Strongest Basic)8.18ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area59.08 ŲChemAxon
Rotatable Bond Count7ChemAxon
Refractivity114.37 m³·mol⁻¹ChemAxon
Polarizability43.65 ųChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0abc-9646000000-04d2eb286617fa811190View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-00xr-3109700000-d386c5de1a87c11cbc6fView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-00di-7973000000-0bc5fc09ba611f5ad1feView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-05fr-8911000000-3f9afe9e89e028c0d258View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0a4i-9003300000-aa0d02f7d6ac5f92863eView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0a4i-9138100000-f2b6df8ef6a8cb7aed70View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0pb9-7951000000-c5814417a1eb6c5de03bView in MoNA
MSMass Spectrum (Electron Ionization)splash10-0ab9-9200000000-b1095b8fe5973d23fdd6View in MoNA
Toxicity Profile
Route of ExposureIntravenous, Oral. Diltiazem is well absorbed from the gastrointestinal tract but undergoes substantial hepatic first-pass effect.
Mechanism of ToxicityPossibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, diltiazem, like verapamil, inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. The resultant inhibition of the contractile processes of the myocardial smooth muscle cells leads to dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue.
MetabolismDiltiazem is metabolized by and acts as an inhibitor of the CYP3A4 enzyme. Half Life: 3.0 - 4.5 hours
Toxicity ValuesLD50=740mg/kg (orally in mice)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the treatment of hypertension.
Minimum Risk LevelNot Available
Health EffectsBecause of its negative inotropic effect, diltiazem causes a modest decrease in heart muscle contractility and reduces myocardium oxygen consumption. Its negative chronotropic effect results in a modest lowering of heart rate, due to slowing of the sinoatrial node. It results in reduced myocardium oxygen consumption. Because of its negative dromotropic effect, conduction through the AV (atrioventricular) node is slowed, which increases the time needed for each beat. This results in reduced myocardium oxygen consumption. A reflex sympathetic response, caused by the peripheral dilation of vessels and the resulting drop in blood pressure, works to counteract the negative inotropic, chronotropic and dromotropic effects of diltiazem. Undesirable effects include hypotension, bradycardia, dizziness, and flushing. (Wikipedia)
SymptomsLD50=740mg/kg (orally in mice)
TreatmentIn the event of overdose or exaggerated response, appropriate supportive measures should be employed in addition to gastrointestinal decontamination. If bradycardia and/or high-degree AV block occurs, administer atropine (0.60 to 1.0 mg). If there is no response to vagal blockage, administer isoproterenol cautiously. Fixed high-degree AV block should be treated with cardiac pacing. In cases of cardiac failure, administer inotropic agents (isoproterenol, dopamine, or dobutamine) and diuretics. If hypotension occurs, use vasopressors (e.g. dopamine or levarterenol bitartrate). (2)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00343
HMDB IDHMDB14487
PubChem Compound ID39186
ChEMBL IDCHEMBL23
ChemSpider ID35850
KEGG IDC06958
UniProt IDNot Available
OMIM ID
ChEBI ID101278
BioCyc IDNot Available
CTD IDNot Available
Stitch IDDiltiazem
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkDiltiazem
References
Synthesis Reference

Kugita, H., Inoue, H., Ikezaki, M. and Takeo, S.; U.S. Patent 3,562,257; assigned to Tanabe Seiyaku Co.,Ltd., Japan.

MSDSLink
General References
  1. Drugs.com [Link]
  2. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

General Function:
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function:
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the delayed rectifying potassium current in heart (IKr). Isoforms USO have no channel activity by themself, but modulates channel characteristics by forming heterotetramers with other isoforms which are retained intracellularly and undergo ubiquitin-dependent degradation.
Gene Name:
KCNH2
Uniprot ID:
Q12809
Molecular Weight:
126653.52 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC5017.3 uMNot AvailableBindingDB 50004704
IC5017.378 uMNot AvailableBindingDB 50004704
IC5017.37801 uMNot AvailableBindingDB 50004704
References
  1. Cavalli A, Poluzzi E, De Ponti F, Recanatini M: Toward a pharmacophore for drugs inducing the long QT syndrome: insights from a CoMFA study of HERG K(+) channel blockers. J Med Chem. 2002 Aug 29;45(18):3844-53. [12190308 ]
  2. Keseru GM: Prediction of hERG potassium channel affinity by traditional and hologram qSAR methods. Bioorg Med Chem Lett. 2003 Aug 18;13(16):2773-5. [12873512 ]
  3. Rajamani R, Tounge BA, Li J, Reynolds CH: A two-state homology model of the hERG K+ channel: application to ligand binding. Bioorg Med Chem Lett. 2005 Mar 15;15(6):1737-41. [15745831 ]
  4. Tobita M, Nishikawa T, Nagashima R: A discriminant model constructed by the support vector machine method for HERG potassium channel inhibitors. Bioorg Med Chem Lett. 2005 Jun 2;15(11):2886-90. [15911273 ]
  5. Jia L, Sun H: Support vector machines classification of hERG liabilities based on atom types. Bioorg Med Chem. 2008 Jun 1;16(11):6252-60. doi: 10.1016/j.bmc.2008.04.028. Epub 2008 Apr 16. [18448342 ]
  6. Ermondi G, Visentin S, Caron G: GRIND-based 3D-QSAR and CoMFA to investigate topics dominated by hydrophobic interactions: the case of hERG K+ channel blockers. Eur J Med Chem. 2009 May;44(5):1926-32. doi: 10.1016/j.ejmech.2008.11.009. Epub 2008 Nov 28. [19110341 ]
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide (PubMed:11159812). Catalyzes 4-beta-hydroxylation of cholesterol. May catalyze 25-hydroxylation of cholesterol in vitro (PubMed:21576599).
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.1 uMNot AvailableBindingDB 50004704
Inhibitory0.5 uMNot AvailableBindingDB 50004704
Inhibitory2.2 uMNot AvailableBindingDB 50004704
IC50217 uMNot AvailableBindingDB 50004704
References
  1. Roy K, Pratim Roy P: Comparative chemometric modeling of cytochrome 3A4 inhibitory activity of structurally diverse compounds using stepwise MLR, FA-MLR, PLS, GFA, G/PLS and ANN techniques. Eur J Med Chem. 2009 Jul;44(7):2913-22. doi: 10.1016/j.ejmech.2008.12.004. Epub 2008 Dec 16. [19128860 ]
  2. Orr ST, Ripp SL, Ballard TE, Henderson JL, Scott DO, Obach RS, Sun H, Kalgutkar AS: Mechanism-based inactivation (MBI) of cytochrome P450 enzymes: structure-activity relationships and discovery strategies to mitigate drug-drug interaction risks. J Med Chem. 2012 Jun 14;55(11):4896-933. doi: 10.1021/jm300065h. Epub 2012 Mar 27. [22409598 ]
  3. Fontana E, Dansette PM, Poli SM: Cytochrome p450 enzymes mechanism based inhibitors: common sub-structures and reactivity. Curr Drug Metab. 2005 Oct;6(5):413-54. [16248836 ]
General Function:
Voltage-gated calcium channel activity
Specific Function:
This protein is a subunit of the dihydropyridine (DHP) sensitive calcium channel. Plays a role in excitation-contraction coupling. The skeletal muscle DHP-sensitive Ca(2+) channel may function only as a multiple subunit complex.
Gene Name:
CACNG1
Uniprot ID:
Q06432
Molecular Weight:
25028.105 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from the brain. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. Implicated in the efflux of numerous drugs and xenobiotics: mitoxantrone, the photosensitizer pheophorbide, camptothecin, methotrexate, azidothymidine (AZT), and the anthracyclines daunorubicin and doxorubicin.
Gene Name:
ABCG2
Uniprot ID:
Q9UNQ0
Molecular Weight:
72313.47 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50851.13804 uMNot AvailableBindingDB 50004704
References
  1. Pick A, Muller H, Wiese M: Structure-activity relationships of new inhibitors of breast cancer resistance protein (ABCG2). Bioorg Med Chem. 2008 Sep 1;16(17):8224-36. doi: 10.1016/j.bmc.2008.07.034. Epub 2008 Jul 20. [18678495 ]
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular Weight:
141477.255 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC5042.658 uMNot AvailableBindingDB 50004704
References
  1. Muller H, Klinkhammer W, Globisch C, Kassack MU, Pajeva IK, Wiese M: New functional assay of P-glycoprotein activity using Hoechst 33342. Bioorg Med Chem. 2007 Dec 1;15(23):7470-9. Epub 2007 Aug 21. [17890094 ]
General Function:
Secondary active organic cation transmembrane transporter activity
Specific Function:
Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnicotinamide (NMN), 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP), the endogenous compounds choline, guanidine, histamine, epinephrine, adrenaline, noradrenaline and dopamine, and the drugs quinine, and metformin. The transport of organic cations is inhibited by a broad array of compounds like tetramethylammonium (TMA), cocaine, lidocaine, NMDA receptor antagonists, atropine, prazosin, cimetidine, TEA and NMN, guanidine, cimetidine, choline, procainamide, quinine, tetrabutylammonium, and tetrapentylammonium. Translocates organic cations in an electrogenic and pH-independent manner. Translocates organic cations across the plasma membrane in both directions. Transports the polyamines spermine and spermidine. Transports pramipexole across the basolateral membrane of the proximal tubular epithelial cells. The choline transport is activated by MMTS. Regulated by various intracellular signaling pathways including inhibition by protein kinase A activation, and endogenously activation by the calmodulin complex, the calmodulin-dependent kinase II and LCK tyrosine kinase.
Gene Name:
SLC22A1
Uniprot ID:
O15245
Molecular Weight:
61153.345 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC5012.4 uMNot AvailableBindingDB 50004704
References
  1. Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergstrom CA, Artursson P: Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1. J Med Chem. 2008 Oct 9;51(19):5932-42. doi: 10.1021/jm8003152. Epub 2008 Sep 13. [18788725 ]