Anagrelide: Difference between revisions

{{Short description|Chemical compound}}

| verifiedrevid = 457129902

| image = Anagrelide2DACS.svg

| alt =

<!-- Clinical data -->

| pregnancy_AU = B3

| routes_of_administration = [[Oral administration|By mouth]]

| legal_AU = S4

| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-generic-medicines-and-biosimilar-medicines-2017 | access-date=30 March 2024}}</ref>

| legal_CA = Rx-only

| legal_UK = POM

| legal_US = Rx-only

| legal_EU = Rx-only

<!-- Pharmacokinetic data -->

| bioavailability =

| metabolism = [[Liver]], partially through CYP1A2

| excretion = Urine (<1%)

<!-- Identifiers -->

| IUPHAR_ligand = 7114

| CAS_number_Ref = {{cascite|correct|??}}

<!-- Chemical data -->

| C=10 | H=7

| Cl=2 | N=3

| O=1

| smiles = O=C1NC2=Nc3c(CN2C1)c(Cl)c(cc3)Cl

'''Anagrelide''' (Agrylin/Xagrid, [[Shire Pharmaceuticals Group|Shire]] and Thromboreductin, AOP Orphan Pharmaceuticals AG) is a drug used for the treatment of [[essential thrombocytosis]] (also known as essential thrombocythemia), or overproduction of blood platelets. It also has been used in the treatment of [[chronic myeloid leukemia]].<ref name="pmid17091608">{{cite journal |vauthors=Voglová J, Maisnar V, Beránek M, Chrobák L |title=[Combination of imatinib and anagrelide in treatment of chronic myeloid leukemia in blastic phase] |language=cs |journal=Vnitr̆ní Lékar̆ství |volume=52 |issue=9 |pages=819–22 |year=2006 |pmid=17091608 }}</ref>

Anagrelide controlled release (GALE-401) is in phase III clinical trials by [[Galena Biopharma]] for the treatment of essential thrombocytosis.<ref>{{cite press release|url=https://globenewswire.com/news-release/2016/12/28/901925/0/en/Galena-Biopharma-Confirms-Regulatory-Pathway-for-GALE-401-Anagrelide-Controlled-Release.html|title=Galena Biopharma Confirms Regulatory Pathway for GALE-401 (Anagrelide Controlled Release)| work = Galena Biopharma, Inc. |date=2016-12-28|via = globenewswire.com }}</ref>

== Medical uses ==

Anagrelide is used to treat [[essential thrombocytosis]], especially when the current treatment of the patient is insufficient.<ref name="HarrisonCN2">{{cite journal | vauthors = 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 | display-authors = 6 | title = Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia | journal = The New England Journal of Medicine | volume = 353 | issue = 1 | pages = 33–45 | date = July 2005 | pmid = 16000354 | doi = 10.1056/NEJMoa043800 | doi-access = free }}</ref> Essential thrombocytosis patients who are suitable for anagrelide often meet one or more of the following factors:<ref name=ReillyJT>{{cite journal | vauthors = Reilly JT | title = Anagrelide for the treatment of essential thrombocythemia: a survey among European hematologists/oncologists | journal = Hematology | volume = 14 | issue = 1 | pages = 1–10 | date = February 2009 | pmid = 19154658 | doi = 10.1179/102453309X385115 | s2cid = 26257327 }}</ref><ref name=BriereJB>{{cite journal | vauthors = Brière JB | title = Essential thrombocythemia | journal = Orphanet Journal of Rare Diseases | volume = 2 | issue = 1 | pages = 3 | date = January 2007 | pmid = 17210076 | pmc = 1781427 | doi = 10.1186/1750-1172-2-3 | doi-access = free }}</ref>

* age over 60 years

* platelet count over 1000×10⁹/[[litre|L]]

* a history of [[thrombosis]]

According to a 2005 [[Medical Research Council (UK)|Medical Research Council]] randomized trial, the combination of [[hydroxyurea]] with [[aspirin]] is superior to the combination of anagrelide and [[aspirin]] for the initial management of essential thrombocytosis. The [[hydroxyurea]] arm had a lower likelihood of [[myelofibrosis]], [[arterial]] [[thrombosis]], and [[bleeding]], but it had a slightly higher rate of [[venous thrombosis]].<ref name="HarrisonCN2" /> Anagrelide can be useful in times when hydroxyurea proves ineffective.

== Side-effects ==

Common [[adverse drug reaction|side effects]] are headache, diarrhea, unusual weakness/fatigue, hair loss, nausea.

The same MRC trial mentioned above also analyzed the effects of anagrelide on bone marrow fibrosis, a common feature in patients with myelofibrosis. The use of anagrelide was associated with a rapid increase in the degree of reticulin deposition (the mechanism by which fibrosis occurs), when compared to those in whom hydroxyurea was used. Patients with myeloproliferative conditions are known to have a very slow and somewhat variable course of marrow fibrosis increase. This trend may be accelerated by anagrelide. This increase in fibrosis appeared to be linked to a drop in hemoglobin as it progressed. Stopping anagrelide (and switching patients to hydroxyurea) appeared to reverse the degree of marrow fibrosis. Thus, patients on anagrelide may need to be monitored on a periodic basis for marrow reticulin scores, especially if anemia develops, or becomes more pronounced if present initially.<ref>{{cite journal |vauthors=Campbell PJ, Bareford D, Erber WN |title=Reticulin accumulation in essential thrombocythemia: prognostic significance and relationship to therapy |journal=J. Clin. Oncol. |volume=27 |issue=18 |pages=2991–9 |date=June 2009 |pmid=19364963 |doi=10.1200/JCO.2008.20.3174 |pmc=3398138 |display-authors=etal }}</ref>

Due to these issues, anagrelide should not generally be considered for first line therapy for essential thrombocytosis.

== Mechanism of action ==

Anagrelide works by inhibiting the maturation of [[platelets]] from [[megakaryocytes]].<ref name="pmid16810615">{{cite journal |author =Petrides PE |title=Anagrelide: what was new in 2004 and 2005? |journal=Semin. Thromb. Hemost. |volume=32 |issue=4 Pt 2 |pages=399–408 |year=2006 |pmid=16810615 |doi=10.1055/s-2006-942760|s2cid=24930286 }}</ref> The exact mechanism of action is unclear, although it is known to be a [[phosphodiesterase inhibitor]].<ref>{{cite journal | pmid = 3027338 | volume=30 | issue=2 | title=Inhibitors of cyclic AMP phosphodiesterase. 1. Analogues of cilostamide and anagrelide |date=February 1987 | journal=J. Med. Chem. | pages=295–303 |vauthors=Jones GH, Venuti MC, Alvarez R, Bruno JJ, Berks AH, Prince A | doi=10.1021/jm00385a011}}</ref> It is a potent ([[IC50|IC₅₀]] = 36nM) inhibitor of [[phosphodiesterase]]-II.{{Citation needed|date=December 2008}} It inhibits PDE-3 and phospholipase A2.<ref>{{cite journal | pmid = 20331456 | doi=10.1111/j.1365-2141.2010.08122.x | volume=149 | issue=3 | title=Guideline for investigation and management of adults and children presenting with a thrombocytosis |date=May 2010 | journal=Br. J. Haematol. | pages=352–75 |vauthors=Harrison CN, Bareford D, Butt N | s2cid=2301197 |display-authors=etal| doi-access=free }}</ref>

== Synthesis ==

{| class="wikitable"

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! Synthesis 1<ref>{{cite patent | country = US | number = 3932407 | inventor = Beverung WN, Partyka A }}; {{cite patent |country=US |number= 31617}}; T. A. Jenks et al., {{US patent|4146718}} (1976, 1984, 1979 all to [[Bristol-Myers]]).</ref><ref>{{cite journal|doi=10.1002/jhet.5570180114|title=Synthesis and reactions of 2-chloro-3,4-dihydrothienopyrimidines and -quinazolines|journal=Journal of Heterocyclic Chemistry|volume=18|pages=67–70|year=1981| vauthors = Yamaguchi H, Ishikawa F }}</ref> !! Synthesis 2

|-

| [[File:Anagrelide-synthesis.svg|thumb|500px]] || [[File:Anagrelide synthesis.svg|500px]]

|}

Condensation of benzyl chloride '''1''' with ethyl ester of glycine gives alkylated product '''2'''. Reduction of the nitro group leads to the aniline and reaction of this with [[cyanogen bromide]] possibly gives cyanamide '''3''' as the initial intermediate. Addition of the aliphatic would then lead to formation of the [[quinazoline]] ring ('''4'''). Amide formation between the newly formed imide and the ester would then serve to form the imidazolone ring, whatever the details of the sequence, there is obtained anagrelide ('''5''').

== References ==

{{reflist}}

{{Phosphodiesterase inhibitors}}

[[Category:Drugs with unknown mechanisms of action]]

[[Category:Chloroarenes]]

[[Category:Drugs developed by Takeda Pharmaceutical Company]]

[[Category:tricyclic compounds]]