Anagrelide

Names

[ Name ]:
Anagrelide

[Synonym ]:
[14C]-Anagrelide
BL 4162A
Anagrelide (INN/BAN)
6,7-di-chloro-1,5-dihydroimidazo[2,1-b]quinazolin-2[3 H ]-one base
Imidazo[2,1-b]quinazolin-2(3H)-one, 6,7-dichloro-5,10-dihydro-
Anagrelida
UNII-K9X45X0051
6,7-Dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one
Anagrelide
6,7-Dichloro-5,10-dihydroimidazo[2,1-b]quinazolin-2(3H)-one
Anagrelidum
6,7-dichloro-5,10-dihydro-3H-imidazo[2,1-b]quinazolin-2-one
Anagrelidum [INN-Latin]
Agrelin
MFCD00866794
6,7-dichloro-1,5-dihydro-imidazo[2,1-b]quinazolin-2-one
6,7-Dichloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one
Anagrelida [INN-Spanish]

Biological Activity

[Description]:

Anagrelide, an inhibitor of phosphodiesterase type III (PDEIII) (IC50=36 nM), inhibits platelet production. Anagrelide, an imidazoquinazoline derivative, acts as an inhibitor of platelet aggregation. Anagrelide plays in the antithrombopoietic action. The platelet-lowering agent[1].

[Related Catalog]:

Research Areas >> Cancer

Research Areas >> Cardiovascular Disease

Signaling Pathways >> Metabolic Enzyme/Protease >> Phosphodiesterase (PDE)

[Target]

PDEIII[1]

[In Vitro]

Anagrelide potently inhibits the development of marrow megakaryocytes (IC50=26 nM)[1]. Anagrelide is a distinct pharmacological agent that inhibit bone marrow megakaryocytopoiesis. Anagrelide (0.05, 0.3, 1 µM) inhibits only megakaryocytic cell growth not non-megakaryocytic cells. Anagrelide shifts cell growth to the non-megakaryocytic compartment, an effect that suggested that it was devoid of cytotoxic activity[2]. Anagrelide induces a cytotoxic effect in the GIST882 cell line at a submicromolar concentration (IC50= 16 nM), but Anagrelide is only weakly active in the GIST48 cell line[3].Anagrelide decreases gastrointestinal stromal tumor (GIST) cell proliferation and promotes their apoptosis in vitro[3]. Cell Proliferation Assay[2] Cell Line: Megakaryocytic and non-megakaryocytic cells Concentration: 0.05, 0.3, 1 µM Incubation Time: 12-day Result: Inhibited only megakaryocytic cell growth at every concentration tested

[In Vivo]

Anagrelide is effective in a GIST xenograft mouse model with KIT exon 9 mutation that may pose a therapeutic challenge, as these GISTs require a high daily dose of Imatinib[3].Anagrelide inhibits GIST growth in patient-derived mouse xenograft models. Anagrelide has therapeutic value in the treatment of GIST.Anagrelide has antitumoral activity in GIST xenograft models[3]. Anagrelide (5 mg/kg/bid) inhibits or reduces tumor growth in GIST2B, GIST9, GIST882 model models[3]. Animal Model: Adult female athymic mice bearing GIST2B, GIST3, GIST9, GIST882 model[3] Dosage: 5 mg/kg/bid Administration: Treated with 5 mg/kg/bid or with the combination of Anagrelide and Imatinib (given at the same dose and schedule as the single agents); for 10 days Result: Inhibited or reduced tumor growth in three (GIST2B, GIST9, GIST882) of these four models. The most potent effect was observed in the GIST2B model that harbors a KIT exon 9 mutation leading to p.A502_Y503 duplication. Reduced the tumor volume 68% after 10 days of therapy in this model.

[References]

[1]. Guosu Wang, et al. Comparison of the biological activities of Anagrelide and its major metabolites in haematopoietic cell cultures. Br J Pharmacol. 2005 Oct;146(3):324-32.

[2]. Y Hong, et al. Comparison between Anagrelide and hydroxycarbamide in their activities against haematopoietic progenitor cell growth and differentiation: selectivity of Anagrelide for the megakaryocytic lineage. Leukemia. 2006 Jun;20(6):1117-22.

[3]. Olli-Pekka Pulkka, et al. Anagrelide for Gastrointestinal Stromal Tumor. Clin Cancer Res. 2019 Mar 1;25(5):1676-1687.

Chemical & Physical Properties

[ Density]:
1.8±0.1 g/cm3

[ Boiling Point ]:
376.5±52.0 °C at 760 mmHg

[ Melting Point ]:
280 °C

[ Molecular Formula ]:
C₁₀H₇Cl₂N₃O

[ Molecular Weight ]:
256.088

[ Flash Point ]:
181.5±30.7 °C

[ Exact Mass ]:
254.996613

[ PSA ]:
44.70000

[ LogP ]:
1.96

[ Vapour Pressure ]:
0.0±0.9 mmHg at 25°C

[ Index of Refraction ]:
1.791

[ Storage condition ]:
2-8°C

[ Water Solubility ]:
slightly soluble

Toxicological Information

CHEMICAL IDENTIFICATION

RTECS NUMBER :: NJ5903150

CHEMICAL NAME :: Imidazo(2,1-b)quinazolin-2(3H)-one, 6,7-dichloro-1,5-dihydro-

CAS REGISTRY NUMBER :: 68475-42-3

LAST UPDATED :: 199612

DATA ITEMS CITED :: 1

MOLECULAR FORMULA :: C10-H7-Cl2-N3-O

MOLECULAR WEIGHT :: 256.10

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Unreported

SPECIES OBSERVED :: Human

DOSE/DURATION :: 300 ug/kg/7D

TOXIC EFFECTS :: Behavioral - headache Gastrointestinal - other changes

REFERENCE :: PAACA3 Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- Volume(issue)/page/year: 29,212,1988

Safety Information

[ Safety Phrases ]:
S3-S7

[ RIDADR ]:
3163

[ Hazard Class ]:
2.2

[ HS Code ]:
2933990090

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Customs

[ HS Code ]: 2933990090

[ Summary ]:
2933990090. heterocyclic compounds with nitrogen hetero-atom(s) only. VAT:17.0%. Tax rebate rate:13.0%. . MFN tariff:6.5%. General tariff:20.0%