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Identification
NameAnagrelide
Accession NumberDB00261  (APRD00798)
TypeSmall Molecule
GroupsApproved
Description

Anagrelide is a drug used for the treatment of essential thrombocytosis (ET; essential thrombocythemia). It also has been used in the treatment of chronic myeloid leukemia. [Wikipedia]

Structure
Thumb
Synonyms
Anagrelida
Anagrelidum
External Identifiers
  • BL-4162A
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Agrylincapsule.5 mg/1oralShire US Manufacturing Inc.1997-03-14Not applicableUs
Agrylincapsule0.5 mgoralShire Pharma Canada Ulc1998-01-06Not applicableCanada
Dom-anagrelidecapsule0.5 mgoralDominion Pharmacal2006-08-02Not applicableCanada
Mylan-anagrelidecapsule0.5 mgoralMylan Pharmaceuticals Ulc2005-04-11Not applicableCanada
PHL-anagrelidecapsule0.5 mgoralPharmel Inc2006-07-212009-10-26Canada
PMS-anagrelidecapsule0.5 mgoralPharmascience Inc2006-01-06Not applicableCanada
Sandoz Anagrelidecapsule0.5 mgoralSandoz Canada Incorporated2004-11-05Not applicableCanada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Anagrelide Hydrochloridecapsule1 mg/1oralIVAX Pharmaceuticals, Inc.2005-04-18Not applicableUs
Anagrelide Hydrochloridecapsule.5 mg/1oralAvera Mc Kennan Hospital2015-07-15Not applicableUs
Anagrelide Hydrochloridecapsule.5 mg/1oralCarilion Materials Management2005-04-18Not applicableUs
Anagrelide Hydrochloridecapsule.5 mg/1oralPhysicians Total Care, Inc.2007-07-19Not applicableUs
Anagrelide Hydrochloridecapsule.5 mg/1oralIVAX Pharmaceuticals, Inc.2005-04-18Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
XagridNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Anagrelide Hydrochloride
58579-51-4
Thumb
  • InChI Key: TVWRQCIPWUCNMI-UHFFFAOYSA-N
  • Monoisotopic Mass: 290.973295014
  • Average Mass: 292.549
DBSALT000379
Categories
UNIIK9X45X0051
CAS number68475-42-3
WeightAverage: 256.088
Monoisotopic: 254.996617275
Chemical FormulaC10H7Cl2N3O
InChI KeyInChIKey=OTBXOEAOVRKTNQ-UHFFFAOYSA-N
InChI
InChI=1S/C10H7Cl2N3O/c11-6-1-2-7-5(9(6)12)3-15-4-8(16)14-10(15)13-7/h1-2H,3-4H2,(H,13,14,16)
IUPAC Name
6,7-dichloro-1H,2H,3H,5H-imidazolidino[2,1-b]quinazolin-2-one
SMILES
ClC1=CC=C2N=C3NC(=O)CN3CC2=C1Cl
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as quinazolines. These are compounds containing a quinazoline moiety, which is made up of two fused six-member aromatic rings, a benzene ring and a pyrimidine ring.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassNaphthyridines
Sub ClassQuinazolines
Direct ParentQuinazolines
Alternative Parents
Substituents
  • Quinazoline
  • 1,2-dichlorobenzene
  • Chlorobenzene
  • Benzenoid
  • Imidazolidinone
  • Aryl halide
  • Aryl chloride
  • Imidazolidine
  • Tertiary amine
  • Guanidine
  • Carboxamide group
  • Azacycle
  • Organic 1,3-dipolar compound
  • Propargyl-type 1,3-dipolar organic compound
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of patients with thrombocythemia, secondary to myeloproliferative disorders, to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms including thrombo-hemorrhagic events.
PharmacodynamicsAnagrelide is a drug used for the treatment of essential thrombocytosis (ET; essential thrombocythemia). It works by inhibiting the maturation of megakaryocytes into platelets. The exact mechanism of action is unclear, although it is known to be a potent (IC50 = 36nM) inhibitor of phosphodiesterase-III.
Mechanism of actionThe mechanism by which anagrelide reduces blood platelet count is still under investigation. Studies in patients support a hypothesis of dose-related reduction in platelet production resulting from a decrease in megakaryocyte hypermaturation. In blood withdrawn from normal volunteers treated with anagrelide, a disruption was found in the postmitotic phase of megakaryocyte development and a reduction in megakaryocyte size and ploidy. At therapeutic doses, anagrelide does not produce significant changes in white cell counts or coagulation parameters, and may have a small, but clinically insignificant effect on red cell parameters. Anagrelide inhibits cyclic AMP phosphodiesterase III (PDEIII). PDEIII inhibitors can also inhibit platelet aggregation. However, significant inhibition of platelet aggregation is observed only at doses of anagrelide higher than those required to reduce platelet count.
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Extensive, with < 1% recovered unchanged in the urine. Metabolized primarily in the liver by cytochrome P450 1A2 (CYP1A2). Recently, it was found that anagrelide is bio-transformed in humans into two major metabolites (6,7-dichloro-3-hydroxy-1,5 dihydro-imidazo[2,1-b]quinazolin-2-one (BCH24426) and 2-amino-5,6-dichloro-3,4,-dihydroquinazoline (RL603). Whether these metabolites have biological activities that may underlie the mode of action of the parent drug is presently unclear.

SubstrateEnzymesProduct
Anagrelide
Not Available
2-amino-5,6-dichloro-3,4,-dihydroquinazolineDetails
Anagrelide
Not Available
6,7-dichloro-3-hydroxy-1,5 dihydro-imidazo[2,1-b]quinazolin-2-oneDetails
Route of eliminationNot Available
Half lifeAt fasting and at a dose of 0.5 mg of anagrelide, the plasma half-life is 1.3 hours.
ClearanceNot Available
ToxicityThere are no reports of overdosage with anagrelide, however thrombocytopenia, which can potentially cause bleeding, is expected from overdosage. Single oral doses of anagrelide at 2,500, 1,500 and 200 mg/kg in mice, rats and monkeys, respectively, were not lethal. Symptoms of acute toxicity were: decreased motor activity in mice and rats and softened stools and decreased appetite in monkeys.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9972
Blood Brain Barrier+0.848
Caco-2 permeable+0.5826
P-glycoprotein substrateSubstrate0.7133
P-glycoprotein inhibitor INon-inhibitor0.5302
P-glycoprotein inhibitor IINon-inhibitor0.8438
Renal organic cation transporterInhibitor0.7044
CYP450 2C9 substrateNon-substrate0.8171
CYP450 2D6 substrateNon-substrate0.7564
CYP450 3A4 substrateSubstrate0.725
CYP450 1A2 substrateInhibitor0.688
CYP450 2C9 inhibitorNon-inhibitor0.7769
CYP450 2D6 inhibitorNon-inhibitor0.736
CYP450 2C19 inhibitorNon-inhibitor0.6425
CYP450 3A4 inhibitorNon-inhibitor0.5974
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6563
Ames testNon AMES toxic0.6107
CarcinogenicityNon-carcinogens0.8902
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.8127 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8386
hERG inhibition (predictor II)Non-inhibitor0.8405
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Shire development inc
  • Alphapharm pty ltd
  • Barr laboratories inc
  • Impax laboratories inc
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Mylan laboratories inc
  • Roxane laboratories inc
  • Sandoz inc
  • Watson laboratories
Packagers
Dosage forms
FormRouteStrength
Capsuleoral.5 mg/1
Capsuleoral1 mg/1
Capsuleoral0.5 mg
Prices
Unit descriptionCostUnit
Agrylin 1 mg capsule13.03USD each
Anagrelide hcl 1 mg capsule11.91USD each
Agrylin 0.5 mg capsule7.37USD each
Anagrelide hcl 0.5 mg capsule5.94USD each
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point280 °CNot Available
water solubilityVery slightly solubleNot Available
logP2.4Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.279 mg/mLALOGPS
logP1.95ALOGPS
logP1.94ChemAxon
logS-3ALOGPS
pKa (Strongest Acidic)12.55ChemAxon
pKa (Strongest Basic)3.62ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area44.7 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity63.25 m3·mol-1ChemAxon
Polarizability23.61 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
References
Synthesis Reference

DrugSyn.org

US3932407
General References
  1. Voglova J, Maisnar V, Beranek M, Chrobak L: [Combination of imatinib and anagrelide in treatment of chronic myeloid leukemia in blastic phase]. Vnitr Lek. 2006 Sep;52(9):819-22. [PubMed:17091608 ]
  2. Petrides PE: Anagrelide: what was new in 2004 and 2005? Semin Thromb Hemost. 2006 Jun;32(4 Pt 2):399-408. [PubMed:16810615 ]
  3. Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D, Wilkins BS, van der Walt JD, Reilly JT, Grigg AP, Revell P, Woodcock BE, Green AR: Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005 Jul 7;353(1):33-45. [PubMed:16000354 ]
External Links
ATC CodesL01XX35
AHFS Codes
  • 10:00.00
  • 92:00.00
PDB EntriesNot Available
FDA labelDownload (295 KB)
MSDSDownload (97.3 KB)
Interactions
Drug Interactions
Drug
AbciximabAnagrelide may increase the anticoagulant activities of Abciximab.
AcenocoumarolAnagrelide may increase the anticoagulant activities of Acenocoumarol.
Acetylsalicylic acidThe risk or severity of adverse effects can be increased when Anagrelide is combined with Acetylsalicylic acid.
AlteplaseAnagrelide may increase the anticoagulant activities of Alteplase.
AnistreplaseAnagrelide may increase the anticoagulant activities of Anistreplase.
ApixabanThe risk or severity of adverse effects can be increased when Anagrelide is combined with Apixaban.
CilostazolThe risk or severity of adverse effects can be increased when Anagrelide is combined with Cilostazol.
CitalopramCitalopram may increase the QTc-prolonging activities of Anagrelide.
Citric AcidAnagrelide may increase the anticoagulant activities of Citric Acid.
CollagenaseThe risk or severity of adverse effects can be increased when Anagrelide is combined with Collagenase.
Dabigatran etexilateAnagrelide may increase the anticoagulant activities of Dabigatran etexilate.
DalteparinAnagrelide may increase the anticoagulant activities of Dalteparin.
Deoxycholic AcidThe risk or severity of adverse effects can be increased when Anagrelide is combined with Deoxycholic Acid.
DicoumarolAnagrelide may increase the anticoagulant activities of Dicoumarol.
DofetilideDofetilide may increase the QTc-prolonging activities of Anagrelide.
Edetic AcidAnagrelide may increase the anticoagulant activities of Edetic Acid.
EnoxaparinAnagrelide may increase the anticoagulant activities of Enoxaparin.
Ethyl biscoumacetateAnagrelide may increase the anticoagulant activities of Ethyl biscoumacetate.
Fondaparinux sodiumAnagrelide may increase the anticoagulant activities of Fondaparinux sodium.
GlucosamineGlucosamine may increase the antiplatelet activities of Anagrelide.
GoserelinGoserelin may increase the QTc-prolonging activities of Anagrelide.
HeparinAnagrelide may increase the anticoagulant activities of Heparin.
Ibritumomab tiuxetanThe risk or severity of adverse effects can be increased when Anagrelide is combined with Ibritumomab.
IbrutinibThe risk or severity of adverse effects can be increased when Ibrutinib is combined with Anagrelide.
IvabradineIvabradine may increase the QTc-prolonging activities of Anagrelide.
LeuprolideLeuprolide may increase the QTc-prolonging activities of Anagrelide.
LimaprostLimaprost may increase the antiplatelet activities of Anagrelide.
MifepristoneMifepristone may increase the QTc-prolonging activities of Anagrelide.
ObinutuzumabThe risk or severity of adverse effects can be increased when Anagrelide is combined with Obinutuzumab.
OctreotideOctreotide may increase the QTc-prolonging activities of Anagrelide.
Omega-3 fatty acidsOmega-3 fatty acids may increase the antiplatelet activities of Anagrelide.
Pentosan PolysulfateThe risk or severity of adverse effects can be increased when Pentosan Polysulfate is combined with Anagrelide.
PentoxifyllinePentoxifylline may increase the antiplatelet activities of Anagrelide.
PhenelzinePhenelzine may increase the orthostatic hypotensive activities of Anagrelide.
PhenindioneAnagrelide may increase the anticoagulant activities of Phenindione.
PhenprocoumonAnagrelide may increase the anticoagulant activities of Phenprocoumon.
ReteplaseAnagrelide may increase the anticoagulant activities of Reteplase.
RidogrelAnagrelide may increase the anticoagulant activities of Ridogrel.
RiociguatAnagrelide may increase the hypotensive activities of Riociguat.
RivaroxabanAnagrelide may increase the anticoagulant activities of Rivaroxaban.
StreptokinaseAnagrelide may increase the anticoagulant activities of Streptokinase.
SulodexideAnagrelide may increase the anticoagulant activities of Sulodexide.
TenecteplaseAnagrelide may increase the anticoagulant activities of Tenecteplase.
TipranavirTipranavir may increase the antiplatelet activities of Anagrelide.
TositumomabThe risk or severity of adverse effects can be increased when Anagrelide is combined with Tositumomab.
TranylcypromineTranylcypromine may increase the orthostatic hypotensive activities of Anagrelide.
TreprostinilAnagrelide may increase the anticoagulant activities of Treprostinil.
UrokinaseAnagrelide may increase the anticoagulant activities of Urokinase.
Vitamin EVitamin E may increase the antiplatelet activities of Anagrelide.
WarfarinAnagrelide may increase the anticoagulant activities of Warfarin.
Food Interactions
  • Food appears to reduce the area under the curve by 13.8%, without clinical consequence.
  • Take without regard to meals.

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Metal ion binding
Specific Function:
Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.
Gene Name:
PDE3A
Uniprot ID:
Q14432
Molecular Weight:
124978.06 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423 ]
  3. Venuti MC, Stephenson RA, Alvarez R, Bruno JJ, Strosberg AM: Inhibitors of cyclic AMP phosphodiesterase. 3. Synthesis and biological evaluation of pyrido and imidazolyl analogues of 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline. J Med Chem. 1988 Nov;31(11):2136-45. [PubMed:2846839 ]
  4. 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:
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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 unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N...
Gene Name:
CYP1A2
Uniprot ID:
P05177
Molecular Weight:
58293.76 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 ]
Comments
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Drug created on June 13, 2005 07:24 / Updated on October 08, 2013 14:22