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Identification
NameArgatroban
Accession NumberDB00278  (APRD00105)
Typesmall molecule
Groupsapproved, investigational
Description

Argatroban is a direct, selective thrombin inhibitor. The American College of Cardiologists (ACC) recommend using bivalirudin or argatroban in patients who have had, or at risk for, heparin induced thrombocytopenia (HIT) and are undergoing percutaneous coronary intervention. Argatroban is a non-heparin anticoagulant shown to both normalize platelet count in patients with HIT and prevent the formation of thrombi. Parental anticoagulants must be stopped and a baseline activated partial thromboplastin time must be obtained prior to administering argatroban.

Structure
Thumb
SynonymsNot Available
SaltsNot Available
Brand namesNot Available
Brand mixturesNot Available
CategoriesNot Available
CAS number74863-84-6
WeightAverage: 508.634
Monoisotopic: 508.246788982
Chemical FormulaC23H36N6O5S
InChI KeyKXNPVXPOPUZYGB-XYVMCAHJSA-N
InChI
InChI=1S/C23H36N6O5S/c1-14-8-10-29(18(12-14)22(31)32)21(30)17(6-4-9-26-23(24)25)28-35(33,34)19-7-3-5-16-11-15(2)13-27-20(16)19/h3,5,7,14-15,17-18,27-28H,4,6,8-13H2,1-2H3,(H,31,32)(H4,24,25,26)/t14-,15-,17+,18-/m1/s1
IUPAC Name
(2R,4R)-1-[(2S)-5-[(diaminomethylidene)amino]-2-[(3R)-3-methyl-1,2,3,4-tetrahydroquinoline-8-sulfonamido]pentanoyl]-4-methylpiperidine-2-carboxylic acid
SMILES
C[C@@H]1CCN([C@H](C1)C(O)=O)C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganic Acids and Derivatives
ClassCarboxylic Acids and Derivatives
SubclassAmino Acids, Peptides, and Analogues
Direct parentPeptides
Alternative parentsAlpha Amino Acid Amides; Benzenesulfonamides; Hydroquinolines; N-Acylpiperidines; Piperidinecarboxylic Acids; Sulfonyls; Tertiary Carboxylic Acid Amides; Sulfonamides; Guanidines; Tertiary Amines; Carboxylic Acids; Enolates; Polyamines; Amidines; Secondary Amines
Substituentsalpha-amino acid amide; benzenesulfonamide; alpha-amino acid or derivative; tetrahydroquinoline; piperidinecarboxylic acid; n-acyl-piperidine; benzene; piperidine; sulfonyl; tertiary carboxylic acid amide; sulfonamide; sulfonic acid derivative; carboxamide group; guanidine; tertiary amine; secondary amine; carboxylic acid; polyamine; amidine; enolate; amine; organonitrogen compound
Classification descriptionThis compound belongs to the peptides. These are compounds containing an amide derived from two or more amino carboxylic acid molecules (the same or different) by formation of a covalent bond from the carbonyl carbon of one to the nitrogen atom of another.
Pharmacology
IndicationArgatroban is indicated for prevention and treatment of thrombosis caused by heparin induced thrombocytopenia (HIT). It is also indicated for use in patients with, or at risk for, HIT who are undergoing percutaneous coronary intervention.
PharmacodynamicsArgatroban is a synthetic direct thrombin inhibitor derived from L-arginine indicated as an anticoagulant for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia. Argatroban is a direct thrombin inhibitor that reversibly binds to the thrombin active site. Argatroban does not require the co-factor antithrombin III for antithrombotic activity. Argatroban exerts its anticoagulant effects by inhibiting thrombin-catalyzed or -induced reactions, including fibrin formation; activation of coagulation factors V, VIII, and XIII; protein C; and platelet aggregation. Argatroban is highly selective for thrombin with an inhibitory constant (Ki) of 0.04 µM. At therapeutic concentrations, Argatroban has little or no effect on related serine proteases (trypsin, factor Xa, plasmin, and kallikrein). Argatroban is capable of inhibiting the action of both free and clot-associated thrombin.
Mechanism of actionArgatroban exerts its anticoagulant effects by inhibiting thrombin-catalyzed or -induced reactions, including fibrin formation; activation of coagulation factors V, VIII, and XIII; protein C; and platelet aggregation.
AbsorptionBioavailability is 100% (intravenous).
Volume of distribution
  • 174 mL/kg
  • 12.18 L [70-kg adult]
Protein binding54%
Metabolism

Liver via hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring. Age and gender do not substantially affect the pharmacodynamic or pharmacokinetic profile of argatroban.

Route of eliminationArgatroban is excreted primarily in the feces (65%), presumably through biliary secretion; 22% is eliminated via urine.
Half life39 and 51 minutes
Clearance
  • 5.1 L/kg/hr [infusion doses up to 40 mcg/kg/min]
ToxicityExcessive bleeding
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Argatroban Action PathwayDrug actionSMP00276
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.6195
Blood Brain Barrier - 0.8933
Caco-2 permeable - 0.7293
P-glycoprotein substrate Substrate 0.8193
P-glycoprotein inhibitor I Non-inhibitor 0.6701
P-glycoprotein inhibitor II Non-inhibitor 0.6802
Renal organic cation transporter Non-inhibitor 0.8147
CYP450 2C9 substrate Non-substrate 0.5571
CYP450 2D6 substrate Non-substrate 0.8861
CYP450 3A4 substrate Non-substrate 0.5477
CYP450 1A2 substrate Non-inhibitor 0.8849
CYP450 2C9 substrate Non-inhibitor 0.662
CYP450 2D6 substrate Non-inhibitor 0.8789
CYP450 2C19 substrate Non-inhibitor 0.7706
CYP450 3A4 substrate Non-inhibitor 0.8316
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9636
Ames test Non AMES toxic 0.6238
Carcinogenicity Non-carcinogens 0.7551
Biodegradation Not ready biodegradable 0.9966
Rat acute toxicity 1.5767 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9833
hERG inhibition (predictor II) Non-inhibitor 0.6071
Pharmacoeconomics
Manufacturers
  • Pfizer inc
Packagers
Dosage forms
FormRouteStrength
SolutionIntravenous100mg/mL
Prices
Unit descriptionCostUnit
Argatroban 100 mg/ml Solution 2.5ml Vial1546.46USDvial
Argatroban 100 mg/ml vial743.49USDml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States52140521994-06-302014-06-30
Properties
Statesolid
Experimental Properties
PropertyValueSource
logP1Not Available
Predicted Properties
PropertyValueSource
water solubility2.21e-01 g/lALOGPS
logP0.19ALOGPS
logP-0.97ChemAxon
logS-3.4ALOGPS
pKa (strongest acidic)3.07ChemAxon
pKa (strongest basic)10.91ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count9ChemAxon
hydrogen donor count5ChemAxon
polar surface area180.21ChemAxon
rotatable bond count8ChemAxon
refractivity133.54ChemAxon
polarizability53.9ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveNoChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Tomiya Mano, Jin Shiomura, “Argatroban preparations for ophthalmic use.” U.S. Patent US5506241, issued October, 1986.

US5506241
General Reference
  1. Di Nisio M, Middeldorp S, Buller HR: Direct thrombin inhibitors. N Engl J Med. 2005 Sep 8;353(10):1028-40. Pubmed
External Links
ResourceLink
KEGG CompoundC04931
PubChem Compound152951
PubChem Substance46507650
ChemSpider134807
BindingDB50101744
Therapeutic Targets DatabaseDAP000758
PharmGKBPA164745516
Drug Product Database2243835
RxListhttp://www.rxlist.com/cgi/generic2/argatroban.htm
Drugs.comhttp://www.drugs.com/cdi/argatroban.html
WikipediaArgatroban
ATC CodesB01AE03
AHFS Codes
  • 20:12.04.12
PDB EntriesNot Available
FDA labelshow(83.7 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
Ginkgo bilobaAdditive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.
TreprostinilThe prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the anticoagulant, Argatroban. Monitor for increased bleeding during concomitant thearpy.
Food Interactions
  • Herbs and food with anticoagulant/antiplatelet activity. Major interactions may occur with danshen, dong quai, evening primrose oil, gingko, policosanol, willow bark

Targets

1. Prothrombin

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Prothrombin P00734 Details

References:

  1. Kawada T, Okada Y, Hoson M, Endo S, Yokoyama M, Kitanaka Y, Kimura K, Abe H, Yamate N: Argatroban, an attractive anticoagulant, for left heart bypass with centrifugal pump for repair of traumatic aortic rupture. Jpn J Thorac Cardiovasc Surg. 1999 Mar;47(3):104-9. Pubmed
  2. Sakai M, Ohteki H, Narita Y, Naitoh K, Natsuaki M, Itoh T: Argatroban as a potential anticoagulant in cardiopulmonary bypass-studies in a dog model. Cardiovasc Surg. 1999 Mar;7(2):187-94. Pubmed
  3. Jang IK, Brown DF, Giugliano RP, Anderson HV, Losordo D, Nicolau JC, Dutra OP, Bazzino O, Viamonte VM, Norbady R, Liprandi AS, Massey TJ, Dinsmore R, Schwarz RP Jr: A multicenter, randomized study of argatroban versus heparin as adjunct to tissue plasminogen activator (TPA) in acute myocardial infarction: myocardial infarction with novastan and TPA (MINT) study. J Am Coll Cardiol. 1999 Jun;33(7):1879-85. Pubmed
  4. Matsuo T, Kario K, Matsuda S, Yamaguchi N, Kakishita E: Effect of Thrombin Inhibition on Patients with Peripheral Arterial Obstructive Disease: A Multicenter Clinical Trial of Argatroban. J Thromb Thrombolysis. 1995;2(2):131-136. Pubmed
  5. Serebruany VL, Jang IK, Giugliano RP, Massey TJ, Schwarz Jr RP: A Randomized, Blinded Study of Two Doses of Novastan® (Brand of Argatroban) Versus Heparin as Adjunctive Therapy to Recombinant Tissue Plasminogen Activator (Accelerated Administration) in Acute Myocardial Infarction: Rationale and Design of the Myocardial Infarction using Novastan® and T-PA (MINT) Study. J Thromb Thrombolysis. 1998;5(1):49-52. Pubmed
  6. 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 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 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

2. Cytochrome P450 3A5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 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

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:09