496775-61-2 Usage
Description
Eltrombopag, also known as SB-497115-GR, Promacta, and Revolade, is an oral, small-molecule, nonpeptide thrombopoietin (TPO) receptor agonist. It is used to treat thrombocytopenia, a condition characterized by abnormally low platelet counts. Eltrombopag initiates TPO-receptor signaling by interacting with the transmembrane domain of the receptor, inducing the proliferation and differentiation of cells in the megakaryocytic lineage. It is an orange to red solid and is supplied as the ethanolamine salt (also known as eltrombopag olamine). The most common adverse reactions associated with eltrombopag are nausea, vomiting, menorrhagia, myalgia, paresthesia, and cataracts.
Uses
1. Used in Pharmaceutical Industry:
Eltrombopag is used as a treatment for thrombocytopenia, particularly in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. It acts as an agonist of the Thrombopoietin (Tpo) receptor, promoting the production of platelets and helping to alleviate the symptoms of thrombocytopenia.
2. Used in Research and Development:
Eltrombopag is used as a small molecule agonist of the c-mpl (TpoR) receptor with an IC50 of 0.69 μM for the inhibition of hERG K+ channel tail current. In preclinical studies, the compound has been shown to interact selectively with the TPO receptor, making it a valuable tool for research purposes.
3. Used in Drug Synthesis:
Eltrombopag is derived in five synthetic steps starting from 2-bromo-6-nitroanisole, via Suzuki coupling reaction with 3-carboxyphenylboronic acid to a biphenyl intermediate, followed by cleavage of the methyl ether moiety with hydrobromic acid, and reduction of the nitro group to an amino group under catalytic hydrogenation conditions. Subsequently, the amino group is diazotized with sodium nitrite and hydrochloric acid, and the diazonium intermediate is condensed with 1-(3,4-dimethylphenyl)-3-methyl-2,5-dihydro-1H-pyrazol-5-one to produce eltrombopag. This synthesis process is used in the pharmaceutical industry for the production of the drug.
Originator
Ligand Pharmaceuticals (US)
Clinical Use
Thrombopoetin receptor agonist:Treatment of chronic immune idiopathic
thrombocytopenic purpura (ITP)Chronic hepatitis C associated thrombocytopenia
(HCV)Severe aplastic anaemia
Synthesis
The synthesis of?Eltrombopag is as follows:At room temperature, add 8.02g (20.0mmol) compound of formula V, 3.98g (24.0mmol) 3-carboxyphenylboronic acid, 8.48g (80.0mmol) sodium carbonate, 1.46g (2.0mmol) PdCl2dppf into a 250mL three-necked flask, 80mL ethanol, 65mL water, nitrogen protection, heated to 80, reacted for 10h, cooled to room temperature, added 60mL water, filtered, the filtrate was adjusted to pH 1-2 with 2M hydrochloric acid, a red solid was precipitated, filtered, and the filter cake was ethanol/water ( v/v=1:1, 40mL) beating, filtering, and drying to obtain 7.58g, the yield is 85.8%, and the purity is 99.40%.
Drug interactions
Potentially hazardous interactions with other drugs
Ciclosporin: concentration of eltrombopag reduced.
Statins: increased rosuvastatin concentration, may
need to reduce rosuvastatin dose.
Metabolism
Mainly hepatically metabolised through cleavage,
oxidation by cytochrome P450 isoenzymes CYP1A2
and CYP 2C8 and conjugation with glucuronic acid,
glutathione, or cysteine.Approximately 31% of a dose is eliminated in the
urine as metabolites, and about 59% in the faeces (20%
unchanged).
References
1) Xie?et al. (2018), Pharmacological characterization of eltrombopag, a novel orally active human thrombopoietin receptor agonist; J. Cell. Mol. Med.,?22?5367
2) Erickson-Miller?et al.?(2008),?Preclinical activity of eltrombopag (SB-497115), an oral, nonpeptide thrombopoietin receptor agonist; Stem Cells,?27?424
3) Alvarado?et al.?(2019),?Eltrombopag maintains human hematopoietic stem and progenitor cells under inflammatory conditions mediated by IFN-γ; Blood,?133?2043
4) Guenther?et al.?(2019),?Eltrombopag promotes DNA repair in human hematopoietic stem and progenitor cells; Exp. Hematol.?73?1
5) Vlachodimitropoulou?et al.?(2017),?Eltrombopag: a powerful chelator of cellular or extracellular iron (II) alone or combined with a second chelator; Blood,?130?1923
6) Kao?et al.?(2018),?Thrombopoietin receptor-independent stimulation of hematopoietic stem cells by eltrombopag; Science Transl. Med.,?10?eaas9563
Check Digit Verification of cas no
The CAS Registry Mumber 496775-61-2 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 4,9,6,7,7 and 5 respectively; the second part has 2 digits, 6 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 496775-61:
(8*4)+(7*9)+(6*6)+(5*7)+(4*7)+(3*5)+(2*6)+(1*1)=222
222 % 10 = 2
So 496775-61-2 is a valid CAS Registry Number.
InChI:InChI=1/C25H22N4O4/c1-14-10-11-19(12-15(14)2)29-24(31)22(16(3)28-29)27-26-21-9-5-8-20(23(21)30)17-6-4-7-18(13-17)25(32)33/h4-13,26,30H,1-3H3,(H,32,33)/b27-22-
