Eltrombopag
[3'-{(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene]hydrazino}-2'-hydroxy-3-biphenylcarboxylic
acid] is a first-in-class, orally available thrombopoietin-receptor (TpoR)
agonist developed as treatment for conditions characterized by
thrombocytopenia. Eltrombopag stimulates megakaryocyte proliferation and
differentiation [1].
The
activity of Eltrombopag is dependent on expression of the TpoR but does not
compete with endogenous Tpo. In vitro
experiments suggest that Eltrombopag interacts with TpoR at a distance from the
binding site for endogenous Tpo. Thrombopoietin receptor stimulation leads to
activation of the Janus kinase 2 and signal transducer and activator of
transcription (STAT) 5 pathways, ultimately stimulating proliferation and
differentiation of primary human CD34+ bone marrow cells into CD41+
megakaryocytes and increased platelet production.
Eltrombopag: 2D and 3D Structure |
Eltrombopag was initially approved by the U.S. Food and Drug Administration (US-FDA) on November 20, 2008, for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulin therapy, or splenectomy. On August 24, 2015, the FDA approved an oral suspension of Eltrombopag for the treatment of thrombocytopenia in pediatric patients 1 year and older. Prescription is currently controlled through an FDA restricted distribution system, Risk Evaluation and Mitigation Strategy (REMS), to track the long-term safety profile.
Eltrombopag
received FDA breakthrough treatment designation in February 2014 for patients
with aplastic anemia for which immunosuppression has not been successful.
Eltrombopag Synthesis
WO2002057300A1: The patent reports industrial route to synthesize Eltombopag.
Intermediate 1:
Intermediate 2:
Final Synthesis:
Identifications:
Experimental: 1H NMR (300 MHz, d-DMSO)
δ 13.76 (s, 1H), 13.12 (s, 1H), 9.70 (s, 1H), 8.14 (s, 1H), 7.97 (dd, J = 7.7
Hz, 1H), 7.81 (dd, J = 7.7 Hz, 1H), 7.74-7.60 (m, 5H), 7.22-7.13 (m, 3H), 2.34
(s, 3H), 2.27 (s, 3H), 2.23 (s, 3H).
The
mechanism of action of Eltrombopag and preclinical data in rodent models
suggested a potential risk of bone marrow fibrosis in humans. From the interim
analysis of the EXTEND study, 23 out of 44 patients treated with Eltrombopag
for longer than 1 year demonstrated some degree of fibrosis (20 reticulin and 3
collagen). Cytopenia was not reported in any of the 44 patients.
Sideeffects: The principal
nonclinical toxicology findings associated with Eltrombopag administration
include cataracts, renal toxicity and hepatotoxicity.
No
serious adverse events were reported during both the clinical trials in
patients with ITP and thrombocytopenia associated with HCV-related cirrhosis.
The rate of adverse events(AEs) did not differ among those who received the
active drug and those who received placebo, and were not dose related. Headache
has been consistently the most frequently reported adverse event in all Eltrombopag
trials. Other reported AEs (less than 2%) are fatigue, nausea, vomiting, diarrhea,
nasopharyngitis, arthralgia, increased alanine aminotransferase, upper
respiratory tract infection and urinary tract infection.
In
accordance with the boxed warning, serum liver enzymes and liver function tests
should be performed on all patients before initiation of therapy, every 2 weeks
during dose titration and monthly after establishment of a stable dose. A
reduced starting dose of 25 mg is recommended for patients with moderate-
to-severe liver disease.
References:
1. Zhang, Y.; et. al. Eltrombopag: an oral thrombopoietin receptor agonist for the treatment of idiopathic thrombocytopenic purpura. Clin Ther 2011, 33(11), 1560-76. (FMO only)2. Stasi, R. Eltrombopag: the discovery of a second generation thrombopoietin-receptor agonist. Expert Opin Drug Discov 2009 , 4(1), 85-93. (FMO only)
3. Erickson-Miller, C. L.; et. al. Preclinical activity of eltrombopag (SB-497115), an oral, nonpeptide thrombopoietin receptor agonist. Stem Cells 2009, 27(2), 424-30. (free article)
4. Delorme, E. O.; et. al. Regulated activation of cell-membrane receptors by metal-chelating agonists. WO2002057300A1