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Identification
Name Ximelagatran
Accession Number DB04898
Type small molecule
Groups approved, withdrawn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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
H 376/95
Salts Not Available
Brand names
Name Company
Exanta
Exarta
Brand mixtures Not Available
Categories
  • Anticoagulants
  • Antithrombotic Agents
CAS number 192939-46-1
Weight Average: 473.5652
Monoisotopic: 473.263819255
Chemical Formula C24H35N5O5
InChI Key InChIKey=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
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Benzene and Derivatives
  • Polypeptides
Substructures
  • Carboxylic Acids and Derivatives
  • Hydroxy Compounds
  • Acetates
  • Aliphatic and Aryl Amines
  • Amino Ketones
  • Ethers
  • Benzene and Derivatives
  • Polypeptides
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamidines
  • Carboxamides and Derivatives
  • Amino Acids
  • Imines
  • Azetidines
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.
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
Pathway Name SMPDB ID
Smp00279 Ximelagatran Pathway SMP00279
Pharmacoeconomics
Manufacturers Not Available
Packagers Not Available
Dosage forms
Form Route Strength
Tablet Oral
Prices Not Available
Patents Not Available
Properties
State solid
Experimental Properties Not Available
Predicted Properties
Property Value Source
water solubility 8.45e-02 g/l ALOGPS
logP 1.35 ALOGPS
logP 0.87 ChemAxon
logS -3.8 ALOGPS
pKa (strongest acidic) 9.64 ChemAxon
pKa (strongest basic) 5.48 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 7 ChemAxon
hydrogen donor count 4 ChemAxon
polar surface area 146.35 ChemAxon
rotatable bond count 11 ChemAxon
refractivity 126.57 ChemAxon
polarizability 52.15 ChemAxon
References
Synthesis Reference Not 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
Resource Link
PubChem Compound 9574101 Link_out
PubChem Substance 46509040 Link_out
ChemSpider 7848559 Link_out
Therapeutic Targets Database DAP001218 Link_out
PharmGKB PA161748474 Link_out
Wikipedia http://en.wikipedia.org/wiki/Ximelagatran Link_out
ATC Codes
  • B01AE05
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Prothrombin

Pharmacological action: yes
Actions: inhibitor

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

Organism class: human
UniProt ID: P00734 Link_out
Gene: F2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Enzymes

1. Cytochrome P450 2C9

Actions: substrate

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 unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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 February 08, 2013 16:23