NAV

Ximelagatran

Identification

Generic Name
Ximelagatran
DrugBank Accession Number
DB04898
Background

Ximelagatran is an anticoagulant intended to become a replacement for warfarin by overcoming the dietary restrictions, drug interaction, and monitoring issues associated with the former. In 2006, its manufacturer AstraZeneca announced that it would not attempt to market ximelagatran after reports of hepatotoxicity (liver damage) during trials, and to discontinue its distribution in countries where the drug had been approved.

Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Structure
3D
Similar Structures
Weight
Average: 473.5652
Monoisotopic: 473.263819255
Chemical Formula
C24H35N5O5
Synonyms
  • ethyl 2-[[(1R)-1-cyclohexyl-2- [(2S)-2-[[4-(N'-hydroxycarbamimidoyl) phenyl]methylcarbamoyl]azetidin-1-yl]- 2-oxo-ethyl]amino]acetate
  • Ximelagatrán
  • Ximelagatran
  • Ximélagatran
  • Ximelagatranum
External IDs
  • H 376-95
  • H 376/95
  • H 37695
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Pharmacology

Indication

For the treatment of acute deep vein thrombosis.

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Not Available

Mechanism of action

Ximelagatran was the first member of the drug class of direct thrombin inhibitors that can be taken orally. Its effect is solely related to the inhibition of thrombin.

TargetActionsOrganism
AProthrombin
inhibitor
Humans
Absorption

Rapidly absorbed by the small intestine with an oral bioavailability of 20%.

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Ximelagatran is a prodrug, and hence, it requires in vivo conversion to the active agent, melagatran. The activation of ximelagatran is produced in the liver and many other tissues mainly by reactions of dealkylation and dehydroxylation.

Route of elimination

Not Available

Half-life

3-5 hours

Clearance

Not Available

Adverse Effects
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Toxicity

Hepatotoxicity (liver damage) was reported during trials.

Pathways
PathwayCategory
Ximelagatran Action PathwayDrug action
Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
Integrate drug-drug
interactions in your software
AbataceptThe metabolism of Ximelagatran can be increased when combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Ximelagatran.
AbrocitinibThe metabolism of Abrocitinib can be decreased when combined with Ximelagatran.
AceclofenacThe risk or severity of bleeding and hemorrhage can be increased when Aceclofenac is combined with Ximelagatran.
AcemetacinThe risk or severity of bleeding and hemorrhage can be increased when Ximelagatran is combined with Acemetacin.
Food Interactions
  • Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.

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International/Other Brands
Exanta / Exarta

Categories

ATC Codes
B01AE05 — Ximelagatran
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as dipeptides. These are organic compounds containing a sequence of exactly two alpha-amino acids joined by a peptide bond.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Dipeptides
Alternative Parents
Alpha amino acid esters / Alpha amino acid amides / Benzene and substituted derivatives / Tertiary carboxylic acid amides / Amidoximes / Secondary carboxylic acid amides / Carboxylic acid esters / Azetidines / Monocarboxylic acids and derivatives / Dialkylamines
show 5 more
Substituents
Alpha-amino acid amide / Alpha-amino acid ester / Alpha-amino acid or derivatives / Alpha-dipeptide / Amidine / Amidoxime / Amine / Amino acid or derivatives / Aromatic heteromonocyclic compound / Azacycle
show 19 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
ethyl ester, secondary amino compound, carboxamide, azetidines, amidoxime (CHEBI:65172)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
49HFB70472
CAS number
192939-46-1
InChI Key
ZXIBCJHYVWYIKI-PZJWPPBQSA-N
InChI
InChI=1S/C24H35N5O5/c1-2-34-20(30)15-26-21(17-6-4-3-5-7-17)24(32)29-13-12-19(29)23(31)27-14-16-8-10-18(11-9-16)22(25)28-33/h8-11,17,19,21,26,33H,2-7,12-15H2,1H3,(H2,25,28)(H,27,31)/t19-,21+/m0/s1
IUPAC Name
ethyl 2-{[(1R)-1-cyclohexyl-2-[(2S)-2-[({4-[(Z)-N'-hydroxycarbamimidoyl]phenyl}methyl)carbamoyl]azetidin-1-yl]-2-oxoethyl]amino}acetate
SMILES
CCOC(=O)CN[C@@H](C(=O)N1CC[C@H]1C(=O)NCC1=CC=C(C=C1)C(\N)=N\O)C1CCCCC1

References

General References
  1. Eriksson H, Wahlander K, Gustafsson D, Welin LT, Frison L, Schulman S: A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I. J Thromb Haemost. 2003 Jan;1(1):41-7. [Article]
  2. Weitz JI: New anticoagulants for treatment of venous thromboembolism. Circulation. 2004 Aug 31;110(9 Suppl 1):I19-26. [Article]
  3. Francis CW, Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, Peters GR, Roth AW, McElhattan J, Colwell CW Jr: Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med. 2003 Oct 30;349(18):1703-12. [Article]
  4. Bergqvist D, Solhaug JH, Holmdahl L, Eriksson UG, Andersson M, Boberg B, Ogren M: Pharmacokinetics, preliminary efficacy and safety of subcutaneous melagatran and oral ximelagatran : a multicentre study of thromboprophylaxis in elective abdominal surgery. Clin Drug Investig. 2004;24(3):127-36. [Article]
  5. Koscielny J, Kiesewetter H, Jorg I, Harenberg J: Ximelagatran for treatment and prophylaxis of recurrent events in deep vein thrombosis. Clin Appl Thromb Hemost. 2007 Jul;13(3):299-307. [Article]
Human Metabolome Database
HMDB0015603
PubChem Compound
9574101
PubChem Substance
46509040
ChemSpider
7848559
ChEBI
65172
ChEMBL
CHEMBL522038
ZINC
ZINC000012504524
Therapeutic Targets Database
DAP001218
PharmGKB
PA161748474
Wikipedia
Ximelagatran

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
3TerminatedPreventionThromboembolism1
2TerminatedPreventionStroke Prevention in Patients With Atrial Fibrillation1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coated
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0845 mg/mLALOGPS
logP1.35ALOGPS
logP0.87Chemaxon
logS-3.8ALOGPS
pKa (Strongest Acidic)8.7Chemaxon
pKa (Strongest Basic)5.48Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count7Chemaxon
Hydrogen Donor Count4Chemaxon
Polar Surface Area146.35 Å2Chemaxon
Rotatable Bond Count11Chemaxon
Refractivity126.57 m3·mol-1Chemaxon
Polarizability52.18 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.6065
Blood Brain Barrier-0.7499
Caco-2 permeable-0.7534
P-glycoprotein substrateSubstrate0.84
P-glycoprotein inhibitor INon-inhibitor0.755
P-glycoprotein inhibitor IINon-inhibitor0.947
Renal organic cation transporterNon-inhibitor0.7588
CYP450 2C9 substrateNon-substrate0.8632
CYP450 2D6 substrateNon-substrate0.8163
CYP450 3A4 substrateNon-substrate0.597
CYP450 1A2 substrateNon-inhibitor0.8409
CYP450 2C9 inhibitorNon-inhibitor0.7261
CYP450 2D6 inhibitorNon-inhibitor0.844
CYP450 2C19 inhibitorNon-inhibitor0.669
CYP450 3A4 inhibitorNon-inhibitor0.6775
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9157
Ames testNon AMES toxic0.6238
CarcinogenicityNon-carcinogens0.7863
BiodegradationNot ready biodegradable0.8515
Rat acute toxicity2.4109 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9654
hERG inhibition (predictor II)Inhibitor0.6003
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-004j-4982400000-32fe628a565ad95d34f7
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-00fr-0323900000-3a4a8733aa1091d35734
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-00dr-0212900000-b94fdfc809190f07de51
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-05fs-1267900000-89537a80d9674f8c1c79
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0fkc-0219100000-d5d758e20b43b7a328eb
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-053s-4970200000-f3576aac64a832965111
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4l-0292200000-91a0b9e84caf630428d1
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-229.1504999
predicted
DarkChem Lite v0.1.0
[M-H]-225.3894999
predicted
DarkChem Lite v0.1.0
[M-H]-225.2495999
predicted
DarkChem Lite v0.1.0
[M-H]-215.08531
predicted
DeepCCS 1.0 (2019)
[M+H]+227.1895999
predicted
DarkChem Lite v0.1.0
[M+H]+222.9677999
predicted
DarkChem Lite v0.1.0
[M+H]+226.8274999
predicted
DarkChem Lite v0.1.0
[M+H]+217.4809
predicted
DeepCCS 1.0 (2019)
[M+Na]+226.8869999
predicted
DarkChem Lite v0.1.0
[M+Na]+224.5735999
predicted
DarkChem Lite v0.1.0
[M+Na]+224.8681999
predicted
DarkChem Lite v0.1.0
[M+Na]+223.39343
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Details1. Prothrombin
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Thrombospondin receptor activity
Specific Function
Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostas...
Gene Name
F2
Uniprot ID
P00734
Uniprot Name
Prothrombin
Molecular Weight
70036.295 Da
References
  1. Testa L, Bhindi R, Agostoni P, Abbate A, Zoccai GG, van Gaal WJ: The direct thrombin inhibitor ximelagatran/melagatran: a systematic review on clinical applications and an evidence based assessment of risk benefit profile. Expert Opin Drug Saf. 2007 Jul;6(4):397-406. [Article]
  2. Ho SJ, Brighton TA: Ximelagatran: direct thrombin inhibitor. Vasc Health Risk Manag. 2006;2(1):49-58. [Article]
  3. Bergqvist D, Solhaug JH, Holmdahl L, Eriksson UG, Andersson M, Boberg B, Ogren M: Pharmacokinetics, preliminary efficacy and safety of subcutaneous melagatran and oral ximelagatran : a multicentre study of thromboprophylaxis in elective abdominal surgery. Clin Drug Investig. 2004;24(3):127-36. [Article]
  4. Ersdal E, Schutzer KM, Lonnerstedt C, Ohlsson L, Wall U, Eriksson UG: No influence of food on the pharmacokinetics, pharmacodynamics or tolerability of the 24mg and 36mg oral tablet formulations of ximelagatran. Clin Drug Investig. 2005;25(7):425-33. [Article]
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]

Enzymes

Details1. Cytochrome P450 2C9
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Ufer M: Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. Clin Pharmacokinet. 2005;44(12):1227-46. [Article]
  2. Ximelagatran FDA Review [File]

Drug created at October 21, 2007 22:23 / Updated at February 21, 2021 18:51