Identification

Name
Anagrelide
Accession Number
DB00261
Description

Anagrelide is a platelet-reducing agent used to lower dangerously elevated platelet levels (i.e. to treat thrombocythemia) in patients with myeloproliferative neoplasms.9 It is an oral imidazoquinazoline that was first approved for use in the US in 1997.8 It appears to carry a better response rate than other thrombocythemia treatments (e.g. busulfan, hydroxyurea) and may be better tolerated.8

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 256.088
Monoisotopic: 254.996617275
Chemical Formula
C10H7Cl2N3O
Synonyms
  • Anagrelida
  • Anagrelide
  • Anagrelidum
External IDs
  • BL-4162A

Pharmacology

Indication

Anagrelide is indicated for the treatment of thrombocythemia, secondary to malignant neoplasms, to reduce platelet count and the associated risk of thrombosis. It is also beneficial in the amelioration of thrombocythemia symptoms including thrombo-hemorrhagic events.9

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
Learn More
Pharmacodynamics

Anagrelide decreases platelet counts by suppressing transcription factors necessary for the synthesis and maturation of platelet-producing cells.9 The drug itself appears to have a relatively short residence time in the body necessitating twice or four times daily dosing. However, given that the pharmacological effect of anagrelide therapy is reliant on a gradual suppression of platelet-producing cells, it may take 7 to 14 days11 for its administration to be reflected in reduced platelet counts - for this reason any changes to anagrelide doses should not exceed 0.5 mg/day in any one week.9

Evidence from animal studies suggests anagrelide may impair female fertility.9 Female patients of reproductive age should be advised of the potential for adverse effects on fertility prior to initiating therapy.

Mechanism of action

The exact mechanism by which anagrelide lowers platelet count is unclear. Evidence from human trials suggests a dose-related suppression of megakaryocyte maturation, the cells responsible for platelet production - blood drawn from patients receiving anagrelide showed a disruption to the post-mitotic phase of megakaryocyte development and a subsequent reduction in their size and ploidy.11 This may be achieved via indirect suppression of certain transcription factors required for megakaryocytopoeisis, including GATA-1 and FOG-1.9

Anagrelide is a known inhibitor of phosphodiesterase 3A (PDE3A), although its platelet-lowering effects appear unrelated to this inhibition.6 While PDE3 inhibitors, as a class, can inhibit platelet aggregation, this effect is only seen at higher anagrelide doses (i.e. greater than those required to reduce platelet count).9 Modulation of PDE3A has been implicated in causing cell cycle arrest and apoptosis in cancer cells expressing both PDE3A and SLFN12,4 and may be of value in the treatment of gastrointestinal stromal tumours.5

TargetActionsOrganism
AcGMP-inhibited 3',5'-cyclic phosphodiesterase A
inhibitor
Humans
Absorption

Following oral administration, the bioavailability of anagrelide is approximately 70%.9 Given on an empty stomach, the Cmax is reached within 1 hour (Tmax) of administration. Co-administration with food slightly lowers the Cmax and increases the AUC, but not to a clinically significant extent.9

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Anagrelide is extensively metabolized, primarily in the liver by cytochrome P450 1A2 (CYP1A2), into two major metabolites: 6,7-dichloro-3-hydroxy-1,5 dihydro-imidazo[2,1-b]quinazolin-2-one (3-hydroxy anagrelide) and 2-amino-5,6-dichloro-3,4,-dihydroquinazoline (RL603). The 3-hydroxy metabolite is considered pharmacologically active and carries a similar potency and efficacy in regards to its platelet-lowering effects, but inhibits PDE3 with a potency 40x greater than that of the parent drug.9

Hover over products below to view reaction partners

Route of elimination

Following metabolism, urinary excretion of metabolites appears to be the primary means of anagrelide elimination. Less than 1% of an administered dose is recovered in the urine as unchanged parent drug, while approximately 3% and 16-20% of the administered dose is recovered as 3-hydroxy anagrelide and RL603, respectively.9

Half-life

The t1/2 of anagrelide and its active metabolite, 3-hydroxy anagrelide, are approximately 1.5 hours and 2.5 hours, respectively.9

Clearance
Not Available
Adverse Effects
Learn about our commercial Adverse Effects data.
Learn More
Toxicity

The oral LD50 of anagrelide as reported in rats and mice is >1500mg/kg and >2500mg/kg, respectively.10 Symptoms of overdose may include hypotension, sinus tachycardia, and vomiting. As the therapeutic effect of anagrelide (i.e. platelet reduction) is dose-related, significant thrombocytopenia is expected in instances of overdose.9 Treatment of overdose should involve careful monitoring of platelet counts and complications such as bleeding.9 Employ symptomatic and supportive measures if clinically indicated.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Anagrelide can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Anagrelide can be increased when combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Anagrelide.
AbirateroneThe serum concentration of Anagrelide can be increased when it is combined with Abiraterone.
AcebutololThe risk or severity of QTc prolongation can be increased when Acebutolol is combined with Anagrelide.
AceclofenacThe risk or severity of bleeding can be increased when Aceclofenac is combined with Anagrelide.
AcemetacinThe risk or severity of bleeding can be increased when Acemetacin is combined with Anagrelide.
AcenocoumarolThe risk or severity of bleeding can be increased when Anagrelide is combined with Acenocoumarol.
AcetaminophenThe metabolism of Acetaminophen can be decreased when combined with Anagrelide.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Anagrelide.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

    Learn more
  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

    Learn more
  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

    Learn more
  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

    Learn more
Food Interactions
  • Take with or without food. Co-administration with food slightly alters pharmacokinetics, but not to a clinically significant extent.

Products

Product Ingredients
IngredientUNIICASInChI Key
Anagrelide hydrochlorideVNS4435G3958579-51-4TVWRQCIPWUCNMI-UHFFFAOYSA-N
Product Images
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
AgrylinCapsule0.5 mg/1OralShire US Manufacturing Inc.1997-03-14Not applicableUS flag
AgrylinCapsule1 mg/1OralShire1997-03-142008-03-31US flag
AgrylinCapsule0.5 mgOralShire Pharma Canada Ulc1998-01-06Not applicableCanada flag
XagridCapsule0.5 mgOralShire Pharmaceutical Contracts Limited2004-11-16Not applicableEU flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more
  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

    Learn more
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
AnagrelideCapsule1 mg/1OralTorrent Pharmaceuticals Limited2017-06-30Not applicableUS flag
AnagrelideCapsule0.5 mg/1OralTorrent Pharmaceuticals Limited2017-06-30Not applicableUS flag
Anagrelide HydrochlorideCapsule0.5 mg/1OralEon Labs, Inc.2005-04-182012-03-31US flag
Anagrelide HydrochlorideCapsule0.5 mg/1OralAvera McKennan Hospital2015-07-152017-05-24US flag69189 524120180907 15195 yxz3tl
Anagrelide HydrochlorideCapsule1 mg/1OralMylan Pharmaceuticals2011-02-282014-01-31US flag
Anagrelide HydrochlorideCapsule1 mg/1OralTeva Pharmaceuticals USA, Inc.2005-04-18Not applicableUS flag00172 5240 60 nlmimage10 a12dd0fe
Anagrelide HydrochlorideCapsule1 mg/1OralPhysicians Total Care, Inc.2005-08-152011-06-30US flag54868 538520180907 15195 qk97jw
Anagrelide HydrochlorideCapsule0.5 mg/1OralTeva Pharmaceuticals USA, Inc.2005-04-18Not applicableUS flag00172 5241 60 nlmimage10 aa2dd57e
Anagrelide HydrochlorideCapsule1 mg/1OralEon Labs, Inc.2005-04-182012-03-31US flag
Anagrelide HydrochlorideCapsule0.5 mg/1OralMylan Pharmaceuticals2011-02-282014-01-31US flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more
  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

    Learn more

Categories

ATC Codes
L01XX35 — Anagrelide
Drug Categories
Chemical TaxonomyProvided by Classyfire
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
3-imidazoline / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Hydrocarbon derivative / Organic 1,3-dipolar compound / Organic nitrogen compound / Organic oxygen compound
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
imidazoquinazoline (CHEBI:142290)

Chemical Identifiers

UNII
K9X45X0051
CAS number
68475-42-3
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

References

Synthesis Reference

Warren Neil Beverung, Jr., Anthony Partyka, "Optionally substituted 1,2,3,5-tetrahydroimidezo(2,1-b)-quinazolin-2-ones and 6(H)-1,2,3,4-tetrahydropyimido(2,1-b)quinazolin-2-ones." U.S. Patent US3932407A, issued January 1976.

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]
  4. An R, Liu J, He J, Wang F, Zhang Q, Yu Q: PDE3A inhibitor anagrelide activates death signaling pathway genes and synergizes with cell death-inducing cytokines to selectively inhibit cancer cell growth. Am J Cancer Res. 2019 Sep 1;9(9):1905-1921. eCollection 2019. [PubMed:31598394]
  5. Pulkka OP, Gebreyohannes YK, Wozniak A, Mpindi JP, Tynninen O, Icay K, Cervera A, Keskitalo S, Murumagi A, Kulesskiy E, Laaksonen M, Wennerberg K, Varjosalo M, Laakkonen P, Lehtonen R, Hautaniemi S, Kallioniemi O, Schoffski P, Sihto H, Joensuu H: Anagrelide for Gastrointestinal Stromal Tumor. Clin Cancer Res. 2019 Mar 1;25(5):1676-1687. doi: 10.1158/1078-0432.CCR-18-0815. Epub 2018 Dec 7. [PubMed:30530703]
  6. Espasandin YR, Glembotsky AC, Grodzielski M, Lev PR, Goette NP, Molinas FC, Marta RF, Heller PG: Anagrelide platelet-lowering effect is due to inhibition of both megakaryocyte maturation and proplatelet formation: insight into potential mechanisms. J Thromb Haemost. 2015 Apr;13(4):631-42. doi: 10.1111/jth.12850. Epub 2015 Feb 18. [PubMed:25604267]
  7. Gisslinger H, Buxhofer-Ausch V, Hodisch J, Radinoff A, Karyagina E, Kyrcz-Krzemien S, Abdulkadyrov K, Gerbutavicius R, Melikyan A, Burgstaller S, Hus M, Kloczko J, Yablokova V, Tzvetkov N, Calbecka M, Shneyder T, Warzocha K, Jurgutis M, Kaplanov K, Jilma B, Schoergenhofer C, Klade C: A phase III randomized, multicentre, double blind, active controlled trial to compare the efficacy and safety of two different anagrelide formulations in patients with essential thrombocythaemia - the TEAM-ET 2.0 trial. Br J Haematol. 2019 May;185(4):691-700. doi: 10.1111/bjh.15824. Epub 2019 Mar 28. [PubMed:30919941]
  8. Mazzucconi MG, Redi R, Bernasconi S, Bizzoni L, Dragoni F, Latagliata R, Santoro C, Mandelli F: A long-term study of young patients with essential thrombocythemia treated with anagrelide. Haematologica. 2004 Nov;89(11):1306-13. [PubMed:15531452]
  9. FDA Approved Drug Products: Agrylin (anagrelide) oral capsules [Link]
  10. CaymanChem: Anagrelide MSDS [Link]
  11. Health Canada Product Monograph: Agrylin (anagrelide hydrochloride) capsules for oral use [Link]
Human Metabolome Database
HMDB0014406
KEGG Drug
D07455
PubChem Compound
2182
PubChem Substance
46508863
ChemSpider
2097
BindingDB
50000334
RxNav
596724
ChEBI
142290
ChEMBL
CHEMBL760
ZINC
ZINC000003871541
Therapeutic Targets Database
DAP000612
PharmGKB
PA164742986
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Anagrelide
AHFS Codes
  • 20:12.14 — Platelet-reducing Agents
FDA label
Download (295 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentThrombocythemia, Hemorrhagic1
3CompletedNot AvailableEssential Thrombocythemia (ET)1
3CompletedPreventionEssential Thrombocythemia (ET)1
3CompletedTreatmentEssential Thrombocythemia (ET)3
3RecruitingTreatmentEssential Thrombocythemia (ET)1
2Active Not RecruitingTreatmentMPN (Myeloproliferative Neoplasms)1
2CompletedTreatmentEssential Thrombocythemia (ET)1
2CompletedTreatmentMyeloproliferative Neoplasms / Thrombocytosis1
2, 3Active Not RecruitingTreatmentEssential Thrombocythemia (ET)1
1CompletedNot AvailableHealthy Volunteers2

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
Capsule
CapsuleOral1 mg/1
CapsuleOral
CapsuleOral1 MG
CapsuleOral0.5 mg/1
Capsule, coatedOral0.5 mg
Capsule500 mcg
Capsule0.5 mg
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
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

Targets

Kind
Protein
Organism
Humans
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. 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]
  2. An R, Liu J, He J, Wang F, Zhang Q, Yu Q: PDE3A inhibitor anagrelide activates death signaling pathway genes and synergizes with cell death-inducing cytokines to selectively inhibit cancer cell growth. Am J Cancer Res. 2019 Sep 1;9(9):1905-1921. eCollection 2019. [PubMed:31598394]
  3. FDA Approved Drug Products: Agrylin (anagrelide) oral capsules [Link]

Enzymes

Kind
Protein
Organism
Humans
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. 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]
  2. FDA Approved Drug Products: Agrylin (anagrelide) oral capsules [Link]

Drug created on June 13, 2005 07:24 / Updated on October 27, 2020 11:13

Logo pink
Are you a
new drug developer?
Contact us to learn more about our customized products and solutions.
Logo pink
Stay in the know!
As part of our commitment to providing the most up-to-date drug information, we will be releasing #DrugBankUpdates with our newly added curated drug pages.
#DrugBankUpdates