Tuesday, August 30, 2016

Eltrombopag | Thrombopoietin Receptor (TpoR) Agonist | Treatment for Chronic Immune (Idiopathic) Thrombocytopenic Purpura (ITP)

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 was identified from high-throughput screening of small-molecule biarylhydrazone class of compounds collections. Eltrombopag has 1 acidic end, 1 lipophilic end and a metal chelate group in the center, designed in manner for effective biological activity [1, 2].

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.

In 2010, Eltrombopag was approved in Europe for the long-term treatment of adult patients with previously treated chronic ITP.

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:


1H NMR (Estimated) for Eltrombopag

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).

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. 
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.

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