Eltrombopag

Product Overview

Eltrombopag (SB-497115), developed by GlaxoSmithKline and later co-developed with Novartis, is the world’s first and only approved small-molecule non-peptide TPO receptor agonist, marketed as Promacta (US)／Revolade (Europe), ATC code B02BX05.

Structural class: a biarylhydrazone small molecule, with a 3′-hydrazono-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid core; the other end of the hydrazone is linked to a 1-(3,4-dimethylphenyl)-3-methyl-5-pyrazolone unit. The carboxylic acid, phenolic hydroxyl, and hydrazone/pyrazolone structures in the molecule form a metal-chelating site — the key to its receptor-activating mechanism.

Mechanism of action (different from endogenous TPO): eltrombopag does not compete with thrombopoietin for the same receptor binding site; instead, it binds specific amino acid residues within the transmembrane and juxtamembrane domains of the TPO receptor (TpoR／c-Mpl) and coordinates with metal ions (such as Zn²⁺), thereby activating the receptor and triggering downstream JAK2／STAT5 and MAPK signaling pathways, inducing hematopoietic stem cell differentiation toward megakaryocyte progenitors, promoting megakaryocyte proliferation and maturation, and ultimately increasing platelet production. Experimental data: EC50 of 0.27 μM in murine BAF3 cells containing a STAT-activated IRF-1 promoter and a luciferase reporter under the control of human TpoR; activation of STAT5 in N2C-Tpo cells at 30 μM; EC50 of 0.03 μM for stimulating BAF3/hTpoR cell proliferation; EC50 of 0.1 μM for inducing differentiation of bone marrow CD34⁺ cells into CD41⁺ megakaryocytes.

Pharmacokinetic profile: orally administered; plasma protein binding >99.9%; apparent volume of distribution approx. 8.72 L; biological half-life approx. 21–32 hours; 0% of the parent drug is excreted in urine, with approx. 31% excreted in urine as metabolites.

Important medication restriction (arising from its metal-chelating properties): polyvalent cations (iron, calcium, aluminum, magnesium, selenium, zinc) significantly reduce eltrombopag absorption; therefore, antacids, dairy products, mineral supplements, and other products containing polyvalent cations must not be consumed within 4 hours before or after taking this product.

Technical Specifications

• Standards: CHP／USP／EP

• Specification: 0.99 (purity ≥99.0%, HPLC)

• CAS No.: 496775-61-2 (free acid, EINECS 610-469-9, UNII S56D65XJ9G, MDL MFCD20926253); the olamine salt (eltrombopag olamine, the form used in marketed formulations) is 496775-62-3

• Molecular formula: C₂₅H₂₂N₄O₄ (free acid); the olamine salt is C₂₅H₂₂N₄O₄·2(C₂H₇NO)

• Molecular weight: 442.47 (consistent across ChemicalBook, ChemWhat, Biosynth, and Meilunbio); exact mass 442.164

• Appearance: orange to red (orange to dark red) solid powder; some suppliers also describe it as a white to slightly yellow powder

• Purity (HPLC): ≥ 99.0%

• Melting point: 242–244 ℃ (consistent across ChemicalBook, ChemWhat, Guidechem, Meilunbio, and other sources; recommended value). Biosynth separately records 242 ℃ — a simplified statement of the same range, not contradictory. All the above values come from reagent/supplier standards; no official melting point has been found in publicly available CHP／USP／EP texts — it is recommended to label it as an in-house specification when quoting

• Specific optical rotation: not applicable — the molecule contains no chiral center (the E／Z configuration of the hydrazone group is geometric isomerism, not enantiomerism); structural confirmation (NMR, MS) and related-substance controls are used instead

• Chemical name: 3′-[2-[(2Z)-1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazinyl]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid

• Stereochemistry: no chiral centers; the hydrazone group has the (Z) configuration, and azo-hydrazone tautomerism exists within the molecule

• Solubility: soluble in DMSO (up to approx. 55 mg/mL; other sources record 13.2–26 mg/mL, requiring warming/sonication); soluble in ethanol (up to approx. 14 mg/mL; also recorded as 2.39 mg/mL, requiring warming and sonication); practically insoluble in water (practically insoluble in aqueous buffers at pH 1–7.4; slightly soluble in water)

• Acid dissociation constant (pKa): −1.26 ± 0.40 (calculated)

• Calculated physicochemical parameters: density approx. 1.33 g/cm³; boiling point approx. 656.8 ± 65.0 ℃ (calculated); LogP approx. 4.14; topological polar surface area approx. 114.6 Ų; refractive index approx. 1.666

• Marketed dosage forms: film-coated tablets of 25 mg and 50 mg (as eltrombopag; the formulation actually uses the olamine salt)

• Storage conditions: protect from light, store under inert gas, sealed and dry; 2–8 ℃ or freezing at −20 ℃ is recommended; DMSO or ethanol solutions can be stored at −20 ℃ for up to 3 months

Applications

• Chronic immune (idiopathic) thrombocytopenia (ITP): for adult and pediatric patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy, to increase platelet counts and reduce bleeding risk. It is indicated only for patients whose degree of thrombocytopenia and clinical condition genuinely increase the risk of bleeding

• Severe aplastic anemia (SAA): for patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy; the FDA granted it “Breakthrough Therapy” designation for this use

• Thrombocytopenia associated with chronic hepatitis C (CHC): for thrombocytopenia in patients with chronic hepatitis C, to allow the initiation and maintenance of interferon-based standard antiviral therapy

• Efficacy monitoring and discontinuation rules: during dose adjustment, monitor complete blood counts weekly (including platelet count and peripheral blood smear); after a stable dose is established, switch to monthly monitoring; discontinue if the platelet count does not increase after 4 weeks at the maximum dose; also discontinue in the event of important liver function test abnormalities or excessive platelet count responses

• Pharmacology and mechanism research: used for in vitro and in vivo studies of TPO receptor (c-Mpl) agonism, JAK2／STAT5 and MAPK pathway activation, megakaryocyte proliferation and differentiation, and directed differentiation of hematopoietic stem cells toward the megakaryocyte lineage; studies have also explored repurposing potential in antiviral applications (e.g., dengue virus NS2B-NS3 protease inhibition) and apoptosis induction in hepatocellular carcinoma

• Formulation and manufacturing: used in formulation development of film-coated tablets (25 mg, 50 mg) and oral suspensions; because the API is practically insoluble in water and is a BCS class II compound (low solubility), formulations must focus on solubilization and dissolution; key manufacturing control points include related substances (particularly hydrazone E／Z isomers and azo-hydrazone tautomers), assay, polymorphic form, and residual solvents; suitable for analytical method development and validation, stability studies, impurity reference standards, and GMP scale-up and CMO／CDMO contract manufacturing

Safety notice: This product is an active pharmaceutical ingredient (API) intended only for legitimate industrial, research, and pharmaceutical manufacturing use; it is not for end-user clinical use or self-medication guidance. Hepatotoxicity: may cause elevations of serum transaminases and bilirubin; liver function must be routinely tested before and during treatment; discontinue if ALT rises to more than 3 times the upper limit of normal and is progressive, persists for ≥4 weeks, is accompanied by elevated direct bilirubin, or is accompanied by symptoms of liver injury or evidence of hepatic decompensation. Thrombotic/thromboembolic risk: excessive dosing may raise platelet counts to levels that produce thrombotic or thromboembolic complications. Risk of hematologic malignancy: may increase the risk of hematologic malignancies, particularly in patients with myelodysplastic syndromes. Drug interactions: this product is an OATP1B1 transporter inhibitor; concomitant use with OATP1B1 substrates (such as rosuvastatin) requires close monitoring and consideration of dose reduction; polyvalent cations (iron, calcium, aluminum, magnesium, selenium, zinc) significantly reduce its absorption — it must be taken 2 hours before or 4 hours after ingestion of polyvalent cation-containing medications (antacids), dairy products, and mineral supplements. The most common adverse reactions include nausea, vomiting, menorrhagia, myalgia, paresthesia, cataract, dyspepsia, ecchymosis, thrombocytopenia, elevated ALT／AST, and conjunctival hemorrhage; headache, nasopharyngitis, and diarrhea are also common. It may cause fetal harm during pregnancy. The API’s GHS classification includes acute oral toxicity category 4, serious eye damage category 1, specific target organ toxicity (repeated exposure) category 2, and chronic aquatic hazard category 2 (H302／H318／H373／H410). When handling, wear protective gloves, protective clothing, and eye/face protection; avoid dust inhalation and avoid release to the environment.

Product information: please contact us. This information is for reference only.