Identification

Name
Ximelagatran
Accession Number
DB04898
Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Description

Ximelagatran (Exanta® or Exarta®, H 376/95) is an anticoagulant that has been investigated extensively as a replacement for warfarin that would overcome the problematic dietary, drug interaction, and monitoring issues associated with warfarin therapy. 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.

Structure
Thumb
Synonyms
  • Ethyl 2-[[(1R)-1-cyclohexyl-2- [(2S)-2-[[4-(n'-hydroxycarbamimidoyl) phenyl]methylcarbamoyl]azetidin-1-yl]- 2-oxo-ethyl]amino]acetate
  • Exanta
  • Exarta
  • H 376-95
  • H 37695
  • Ximelagatran
  • ximelagatrán
  • Ximelagatranum
External IDs
H 376/95
International/Other Brands
Exanta / Exarta
Categories
UNII
49HFB70472
CAS number
192939-46-1
Weight
Average: 473.5652
Monoisotopic: 473.263819255
Chemical Formula
C24H35N5O5
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

Pharmacology

Indication

For the treatment of acute deep vein thrombosis.

Pharmacodynamics
Not Available
Mechanism of action

Ximelagatran was the first member of the drug class of direct thrombin inhibitors that can be taken orally. It acts solely by inhibiting the actions of thrombin. Ximelagatran is a prodrug, being converted in vivo to the active agent melagatran.

TargetActionsOrganism
AProthrombin
inhibitor
Human
Absorption

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

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Hepatic. Ximelagatran is a prodrug, being converted in vivo to the active agent melagatran. This conversion takes place in the liver and many other tissues through dealkylation and dehydroxylation (replacing the ethyl and hydroxyl groups with hydrogen).

Route of elimination
Not Available
Half life

3-5 hours

Clearance
Not Available
Toxicity

Hepatotoxicity (liver damage) was reported during trials.

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Ximelagatran Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(1,2,6,7-3H)TestosteroneThe therapeutic efficacy of Ximelagatran can be increased when used in combination with (1,2,6,7-3H)Testosterone.
(R)-warfarinThe risk or severity of bleeding can be increased when Ximelagatran is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Ximelagatran is combined with (S)-Warfarin.
1-TestosteroneThe therapeutic efficacy of Ximelagatran can be increased when used in combination with 1-Testosterone.
18-methyl-19-nortestosteroneThe therapeutic efficacy of Ximelagatran can be increased when used in combination with 18-methyl-19-nortestosterone.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Ximelagatran is combined with 4-hydroxycoumarin.
4-HydroxytestosteroneThe therapeutic efficacy of Ximelagatran can be increased when used in combination with 4-Hydroxytestosterone.
5beta-dihydrotestosteroneThe therapeutic efficacy of Ximelagatran can be increased when used in combination with 5beta-dihydrotestosterone.
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.
Food Interactions
Not Available

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. [PubMed:12871538]
  2. Weitz JI: New anticoagulants for treatment of venous thromboembolism. Circulation. 2004 Aug 31;110(9 Suppl 1):I19-26. [PubMed:15339877]
  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. [PubMed:14585938]
  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. [PubMed:17516699]
  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. [PubMed:17636192]
External Links
Human Metabolome Database
HMDB0015603
PubChem Compound
9574101
PubChem Substance
46509040
ChemSpider
7848559
ChEBI
65172
ChEMBL
CHEMBL522038
Therapeutic Targets Database
DAP001218
PharmGKB
PA161748474
Wikipedia
Ximelagatran
ATC Codes
B01AE05 — Ximelagatran

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2TerminatedPreventionStroke Prevention in Patients With Atrial Fibrillation1
3TerminatedPreventionThromboembolism1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
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)9.64ChemAxon
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
Polarizability52.15 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-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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-dipeptide / Alpha-amino acid ester / Alpha-amino acid amide / Alpha-amino acid or derivatives / Monocyclic benzene moiety / Benzenoid / Amidoxime / Tertiary carboxylic acid amide / Amino acid or derivatives / Azetidine
show 19 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
ethyl ester, secondary amino compound, carboxamide, azetidines, amidoxime (CHEBI:65172)

Targets

Kind
Protein
Organism
Human
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. [PubMed:17688383]
  2. Ho SJ, Brighton TA: Ximelagatran: direct thrombin inhibitor. Vasc Health Risk Manag. 2006;2(1):49-58. [PubMed:17319469]
  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. [PubMed:17516699]
  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. [PubMed:17532684]
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Enzymes

Kind
Protein
Organism
Human
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. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Ximelagatran FDA Review [File]

Drug created on October 21, 2007 16:23 / Updated on December 14, 2018 12:40