| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
Avatrombopag targets the thrombopoietin receptor (TPO-R, also known as c-Mpl). It acts as a non-peptide agonist of the TPO receptor. Binding to TPO-R activates the JAK/STAT signaling pathway, particularly STAT3 and STAT5, which promotes the proliferation and differentiation of megakaryocyte progenitor cells into mature megakaryocytes, ultimately leading to increased platelet production.
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| ln Vitro |
Similar to how recombinant human TPO (rhTPO) does, avatrombopag (E5501; AKR-501) hydrochloride selectively targets the TPO receptor and stimulates megakaryocytopoiesis throughout the growth and maturation of megakaryocytes. It has been demonstrated that avatrombopag hydrochloride exclusively affects humans and chimpanzees[1]. In a concentration-dependent manner, avatrombopag hydrochloride (0-100 nM) promotes the growth of Ba/F3 cells that express TPO receptors. In the cells, avatrombopag hydrochloride (0-3 μM) and rhTPO both cause tyrosine phosphorylation of STAT3 and STAT5, as well as threonine phosphorylation of ERK[1]. Megakaryocyte colony formation from human CB CD34+ cells is promoted by avatrombopag hydrochloride in a concentration-dependent manner. For Avatrombopag hydrochloride, the EC50 is 25 nM, and its maximal activity is comparable to that of rhTPO[1].
Avatrombopag is an orally bioactive, non-peptide thrombopoietin receptor (TPO receptor) agonist. It induces proliferation of Ba/F3 cells expressing the thrombopoietin receptor (EC50 = 3.3 nM). It also induces differentiation of hematopoietic progenitor cells into megakaryocytes. Avatrombopag is species-specific and does not cross-react with rodent TPO receptors, limiting preclinical efficacy studies to primates. |
| ln Vivo |
In NOD/SCID mice transplanted with human FL CD34+ cells, avatrombopag hydrochloride (0.3-3 mg/kg; po; daily for 14 days) enhances the amount of human platelets[1].
In vivo, avatrombopag increases platelet production by activating the intracellular signaling system and promotes production of platelets and megakaryocytes from hemopoietic precursor cells. It is an orally active nonpeptide thrombopoietin (TPO) receptor agonist. In clinical settings, it effectively raises platelet counts in patients with ITP and CLD-associated thrombocytopenia. |
| Enzyme Assay |
The specific protocol for TPO-R binding uses a radioligand binding assay with [125I]-TPO. Membranes from Ba/F3 cells expressing human TPO-R are incubated with 50 pM [125I]-TPO and increasing concentrations of avatrombopag hydrochloride (0.1 nM to 10 uM) in binding buffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 0.1% BSA) for 4 hours at 4degC. Bound radioligand is separated by filtration through GF/B filters presoaked in 0.3% PEI. Non-specific binding is determined with 100 nM unlabeled TPO. Ki is calculated from displacement curves.
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| Cell Assay |
For in vitro cellular assays, Ba/F3 cells stably expressing the human thrombopoietin receptor (TPO-R) are cultured in RPMI-1640 medium with 10% FBS. Cells are washed twice with PBS and resuspended in medium without IL-3. Cells are seeded in 96-well plates at 1×10⁴ cells/well. Avatrombopag hydrochloride is added at concentrations ranging from 0.01 nM to 1 uM. Plates are incubated for 72 hours at 37degC. Cell viability is measured by adding 10 uL of WST-1 reagent and incubating for 4 hours, followed by absorbance measurement at 450 nm. EC50 is calculated by non-linear regression analysis (EC50 = 3.3 nM).
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| Animal Protocol |
Animal/Disease Models: NOD/SCID (severe combined immunodeficient) mouse (transplanted with human FL CD34+cells)[1]
Doses: 0.3, 1, and 3 mg/kg Route of Administration: Po; daily for 14 days Experimental Results: Dose-dependently increased the number of human platelets, resulting in approximately a 2.7-fold increase at 1 mg/ kg/d and a 3.0-fold increase at 3 mg/kg/d on day 14 after the start of administration. An in vivo pharmacodynamic protocol for TPO-R agonists uses cynomolgus monkeys (which have TPO-R cross-reactivity). Male cynomolgus monkeys (3-5 kg) are administered avatrombopag hydrochloride orally by gavage at doses of 0.3, 1, or 3 mg/kg once daily for 14 days. Blood samples are collected pre-dose and on days 4, 7, 11, and 14 for complete blood count (CBC) analysis. The primary endpoint is the increase in platelet count from baseline. Human studies use similar protocols with oral administration. |
| ADME/Pharmacokinetics |
Avatrombopag has favorable oral pharmacokinetics. It has an oral bioavailability of approximately 50% in humans. The drug is highly protein bound (>96%) in plasma. Avatrombopag undergoes hepatic metabolism primarily via CYP2C9 and CYP3A4, with a terminal half-life of approximately 18-19 hours in humans. Steady-state is achieved after approximately 6-9 days of once-daily dosing. No dose adjustment is required for renal impairment.
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| Toxicity/Toxicokinetics |
In clinical use, avatrombopag has a well-characterized safety profile. The most common adverse reactions include headache, fatigue, arthralgia, contusion, and epistaxis. Serious adverse events include thrombotic/thromboembolic complications (portal vein thrombosis in CLD patients, arterial thrombosis in ITP patients) due to excessive platelet elevation. Hepatotoxicity is also a potential risk. The drug is contraindicated in patients with known hypersensitivity.
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| References |
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| Additional Infomation |
Avatrombopag (brand name Doptelet®) is an FDA-approved drug. It was approved in 2018 for the treatment of thrombocytopenia in adults with CLD scheduled for a procedure, and in 2019 for chronic ITP. The recommended dosage for CLD is 60 mg once daily for 5 days, and for ITP it is 20 mg once daily. Avatrombopag offers an advantage over earlier TPO-R agonists due to its oral administration and no food effect on absorption.
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| Molecular Formula |
C29H35CL3N6O3S2
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| Molecular Weight |
686.1156
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| Exact Mass |
684.127
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| CAS # |
570403-17-7
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| Related CAS # |
Avatrombopag;570406-98-3;Avatrombopag maleate;677007-74-8;Avatrombopag-d8 hydrochloride
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| PubChem CID |
87588882
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| Appearance |
Off-white to gray solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
43
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| Complexity |
935
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C([H])=C(C([H])=NC=1N1C([H])([H])C([H])([H])C([H])(C(=O)O[H])C([H])([H])C1([H])[H])C(N([H])C1=NC(C2=C([H])C(=C([H])S2)Cl)=C(N2C([H])([H])C([H])([H])N(C([H])([H])C2([H])[H])C2([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C2([H])[H])S1)=O.Cl[H]
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| InChi Key |
JSHJSCRYBTVFTI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C29H34Cl2N6O3S2.ClH/c30-20-15-23(41-17-20)24-27(37-12-10-35(11-13-37)21-4-2-1-3-5-21)42-29(33-24)34-26(38)19-14-22(31)25(32-16-19)36-8-6-18(7-9-36)28(39)40;/h14-18,21H,1-13H2,(H,39,40)(H,33,34,38);1H
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| Chemical Name |
1-[3-chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)-1,3-thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid;hydrochloride
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 8.33 mg/mL (12.14 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.83 mg/mL (1.21 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 8.3 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4575 mL | 7.2874 mL | 14.5747 mL | |
| 5 mM | 0.2915 mL | 1.4575 mL | 2.9149 mL | |
| 10 mM | 0.1457 mL | 0.7287 mL | 1.4575 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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