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Identification
NameXimelagatran
Accession NumberDB04898
Typesmall molecule
Groupsapproved, investigational, withdrawn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
SynonymLanguageCode
H 376/95Not AvailableNot Available
SaltsNot Available
Brand names
NameCompany
ExantaNot Available
ExartaNot Available
Brand mixturesNot Available
Categories
CAS number192939-46-1
WeightAverage: 473.5652
Monoisotopic: 473.263819255
Chemical FormulaC24H35N5O5
InChI KeyInChIKey=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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganic Acids and Derivatives
ClassCarboxylic Acids and Derivatives
SubclassAmino Acids, Peptides, and Analogues
Direct parentAlpha Amino Acid Esters
Alternative parentsAlpha Amino Acid Amides; Azetidinecarboxylic Acids or Derivatives; Benzene and Substituted Derivatives; Tertiary Carboxylic Acid Amides; Carboxylic Acid Esters; Amidoximes; Tertiary Amines; Secondary Carboxylic Acid Amides; Ethers; Carboxylic Acids; Polyamines; Enolates; Dialkylamines
Substituentsazetidinecarboxylic acid or derivative; benzene; tertiary carboxylic acid amide; carboxylic acid ester; tertiary amine; secondary carboxylic acid amide; azetidine; amidoxime group; carboxamide group; amidine; secondary amine; polyamine; ether; enolate; secondary aliphatic amine; carboxylic acid; organonitrogen compound; amine
Classification descriptionThis compound belongs to the alpha amino acid esters. These are ester derivatives of alpha amino acids.
Pharmacology
IndicationFor the treatment of acute deep vein thrombosis.
PharmacodynamicsNot Available
Mechanism of actionXimelagatran 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.
AbsorptionRapidly absorbed by the small intestine with an oral bioavailability of 20%.
Volume of distributionNot Available
Protein bindingNot 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 eliminationNot Available
Half life3-5 hours
ClearanceNot Available
ToxicityHepatotoxicity (liver damage) was reported during trials.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Ximelagatran Action PathwayDrug actionSMP00279
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.6065
Blood Brain Barrier - 0.7499
Caco-2 permeable - 0.7534
P-glycoprotein substrate Substrate 0.84
P-glycoprotein inhibitor I Non-inhibitor 0.755
P-glycoprotein inhibitor II Non-inhibitor 0.947
Renal organic cation transporter Non-inhibitor 0.7588
CYP450 2C9 substrate Non-substrate 0.8632
CYP450 2D6 substrate Non-substrate 0.8163
CYP450 3A4 substrate Non-substrate 0.597
CYP450 1A2 substrate Non-inhibitor 0.8409
CYP450 2C9 substrate Non-inhibitor 0.7261
CYP450 2D6 substrate Non-inhibitor 0.844
CYP450 2C19 substrate Non-inhibitor 0.669
CYP450 3A4 substrate Non-inhibitor 0.6775
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9157
Ames test Non AMES toxic 0.6238
Carcinogenicity Non-carcinogens 0.7863
Biodegradation Not ready biodegradable 0.8515
Rat acute toxicity 2.4109 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9654
hERG inhibition (predictor II) Inhibitor 0.6003
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
TabletOral
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
water solubility8.45e-02 g/lALOGPS
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 area146.35ChemAxon
rotatable bond count11ChemAxon
refractivity126.57ChemAxon
polarizability52.15ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  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
  2. Weitz JI: New anticoagulants for treatment of venous thromboembolism. Circulation. 2004 Aug 31;110(9 Suppl 1):I19-26. Pubmed
  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
  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
  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
External Links
ResourceLink
PubChem Compound9574101
PubChem Substance46509040
ChemSpider7848559
Therapeutic Targets DatabaseDAP001218
PharmGKBPA161748474
WikipediaXimelagatran
ATC CodesB01AE05
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

1. Prothrombin

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Prothrombin P00734 Details

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
  2. Ho SJ, Brighton TA: Ximelagatran: direct thrombin inhibitor. Vasc Health Risk Manag. 2006;2(1):49-58. Pubmed
  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
  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
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

1. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

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. Epub 2009 Nov 24. Pubmed

Comments
Drug created on October 21, 2007 16:23 / Updated on September 16, 2013 17:26