Identification

Name
Anagrelide
Accession Number
DB00261  (APRD00798)
Type
Small Molecule
Groups
Approved
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.

Structure
Thumb
Synonyms
  • Anagrelida
  • Anagrelidum
External IDs
BL-4162A
Product Ingredients
IngredientUNIICASInChI Key
Anagrelide hydrochlorideVNS4435G3958579-51-4TVWRQCIPWUCNMI-UHFFFAOYSA-N
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AgrylinCapsule1 mg/1OralShire1997-03-142008-03-31Us
AgrylinCapsule0.5 mg/1OralShire1997-03-14Not applicableUs
AgrylinCapsule0.5 mgOralShire Pharma Canada Ulc1998-01-06Not applicableCanada
Sandoz AnagrelideCapsule0.5 mgOralSandoz Canada Incorporated2004-11-05Not applicableCanada
XagridCapsule0.5 mgOralShire Pharmaceutical Contracts Limited2004-11-16Not applicableEu
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AnagrelideCapsule1 mg/1OralTorrent Pharmaceuticals Limited2017-06-30Not applicableUs
AnagrelideCapsule0.5 mg/1OralTorrent Pharmaceuticals Limited2017-06-30Not applicableUs
Anagrelide HydrochlorideCapsule0.5 mg/1OralAvera McKennan Hospital2015-07-15Not applicableUs69189 524120180907 15195 yxz3tl
Anagrelide HydrochlorideCapsule0.5 mg/1OralMylan Pharmaceuticals2011-02-282014-01-31Us
Anagrelide HydrochlorideCapsule1 mg/1OralPhysicians Total Care, Inc.2005-08-152011-06-30Us54868 538520180907 15195 qk97jw
Anagrelide HydrochlorideCapsule1 mg/1OralTeva Pharmaceuticals USA, Inc.2005-04-18Not applicableUs00172 5240 60 nlmimage10 a12dd0fe
Anagrelide HydrochlorideCapsule0.5 mg/1OralCarilion Materials Management2005-04-18Not applicableUs68151 295920180907 15195 1v5x46r
Anagrelide HydrochlorideCapsule1 mg/1OralEon Labs, Inc.2005-04-182012-03-31Us
Anagrelide HydrochlorideCapsule0.5 mg/1OralPhysicians Total Care, Inc.2007-07-19Not applicableUs54868 544320180907 15195 bokxt2
Anagrelide HydrochlorideCapsule0.5 mg/1OralTeva Pharmaceuticals USA, Inc.2005-04-18Not applicableUs00172 5241 60 nlmimage10 aa2dd57e
International/Other Brands
Xagrid
Categories
UNII
K9X45X0051
CAS number
68475-42-3
Weight
Average: 256.088
Monoisotopic: 254.996617275
Chemical Formula
C10H7Cl2N3O
InChI Key
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

Pharmacology

Indication

For 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.

Associated Conditions
Pharmacodynamics

Anagrelide 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 action

The 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.

TargetActionsOrganism
AcGMP-inhibited 3',5'-cyclic phosphodiesterase A
inhibitor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not 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.

Route of elimination
Not Available
Half life

At fasting and at a dose of 0.5 mg of anagrelide, the plasma half-life is 1.3 hours.

Clearance
Not Available
Toxicity

There 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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(1,2,6,7-3H)TestosteroneThe therapeutic efficacy of Anagrelide 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 Anagrelide is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Anagrelide is combined with (S)-Warfarin.
1-TestosteroneThe therapeutic efficacy of Anagrelide can be increased when used in combination with 1-Testosterone.
3-isobutyl-1-methyl-7H-xanthineThe serum concentration of 3-isobutyl-1-methyl-7H-xanthine can be increased when it is combined with Anagrelide.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Anagrelide is combined with 4-hydroxycoumarin.
6-O-benzylguanineThe serum concentration of 6-O-benzylguanine can be increased when it is combined with Anagrelide.
7-DeazaguanineThe serum concentration of 7-Deazaguanine can be increased when it is combined with Anagrelide.
7,9-DimethylguanineThe serum concentration of 7,9-Dimethylguanine can be increased when it is combined with Anagrelide.
8-azaguanineThe serum concentration of 8-azaguanine can be increased when it is combined with Anagrelide.
Food Interactions
  • Food appears to reduce the area under the curve by 13.8%, without clinical consequence.
  • Take without regard to meals.

References

Synthesis Reference
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
Human Metabolome Database
HMDB0014406
KEGG Drug
D07455
PubChem Compound
2182
PubChem Substance
46508863
ChemSpider
2097
BindingDB
50000334
ChEBI
142290
ChEMBL
CHEMBL760
Therapeutic Targets Database
DAP000612
PharmGKB
PA164742986
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Anagrelide
ATC Codes
L01XX35 — Anagrelide
AHFS Codes
  • 20:12.14 — Platelet-reducing Agents
FDA label
Download (295 KB)
MSDS
Download (97.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers2
1CompletedTreatmentHealthy Volunteers1
2CompletedTreatmentEssential Thrombocythemia (ET)1
2RecruitingTreatmentEssential Thrombocythemia (ET) / MPN (Myeloproliferative Neoplasms)1
2, 3Active Not RecruitingTreatmentEssential Thrombocythemia (ET)1
3CompletedNot AvailableEssential Thrombocythemia (ET)1
3CompletedTreatmentEssential Thrombocythemia (ET)3
4CompletedTreatmentThrombocythemia, Hemorrhagic1
Not AvailableCompletedNot AvailableEssential Thrombocythemia (ET)1

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
  • Alphapharm Party Ltd.
  • Barr Pharmaceuticals
  • Cipla Ltd.
  • D.M. Graham Laboratories Inc.
  • Eon Labs
  • Genpharm LP
  • Global Pharmaceuticals
  • Impax Laboratories Inc.
  • Ivax Pharmaceuticals
  • Mallinckrodt Inc.
  • Murfreesboro Pharmaceutical Nursing Supply
  • Mylan
  • Physicians Total Care Inc.
  • Resource Optimization and Innovation LLC
  • Shire Inc.
Dosage forms
FormRouteStrength
CapsuleOral1 mg/1
CapsuleOral0.5 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.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)280 °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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

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
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0a4i-0490000000-03df7de701116d2d73fc

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazanaphthalenes
Sub Class
Benzodiazines
Direct Parent
Quinazolines
Alternative Parents
Benzenoids / Aryl chlorides / Imidazolines / Propargyl-type 1,3-dipolar organic compounds / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds / Organonitrogen compounds / Organochlorides / Hydrocarbon derivatives
Substituents
Quinazoline / Aryl chloride / Aryl halide / Benzenoid / 3-imidazoline / Azacycle / Propargyl-type 1,3-dipolar organic compound / Organic 1,3-dipolar compound / Hydrocarbon derivative / Organooxygen compound
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
imidazoquinazoline (CHEBI:142290)

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
Uniprot Name
cGMP-inhibited 3',5'-cyclic phosphodiesterase A
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
Inhibitor
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 un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
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]
  2. Martinez-Selles M, Datino T, Figueiras-Graillet L, Gama JG, Jones C, Franklin R, Fernandez-Aviles F: Cardiovascular safety of anagrelide in healthy subjects: effects of caffeine and food intake on pharmacokinetics and adverse reactions. Clin Drug Investig. 2013 Jan;33(1):45-54. doi: 10.1007/s40261-012-0032-2. [PubMed:23184666]
  3. Anagrelide FDA label [File]

Drug created on June 13, 2005 07:24 / Updated on October 16, 2018 08:24