Avatrombopag (AKR-501) HCl is an orally bioactive, non-peptide thrombopoietin receptor (TPO receptor) agonist (EC50=3.3 nM). Avatrombopag HCl mimics the bioactivity of TPO. Avatrombopag HCl increases platelet production by activating intracellular signaling systems and promotes the production of platelets and megakaryocytes from hematopoietic precursor cells. Avatrombopag HCl is a substrate of cytochrome P450 (CYP) 2C9 and CYP3A.

Physicochemical Properties

Molecular Formula	C29H35CL3N6O3S2
Molecular Weight	686.1156
Exact Mass	684.127
CAS #	570403-17-7
Related CAS #	Avatrombopag;570406-98-3;Avatrombopag maleate;677007-74-8;Avatrombopag-d8 hydrochloride
PubChem CID	87588882
Appearance	Off-white to gray solid powder
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	10
Rotatable Bond Count	7
Heavy Atom Count	43
Complexity	935
Defined Atom Stereocenter Count	0
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]
InChi Key	JSHJSCRYBTVFTI-UHFFFAOYSA-N
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
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
HS Tariff Code	2934.99.9001
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)

Biological Activity

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].
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].
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.
References	[1]. AKR-501 (YM477) a novel orally-active thrombopoietin receptor agonist. Eur J Haematol. 2009;82(4):247-254. [2]. Avatrombopag for the treatment of thrombocytopenia in patients with chronic liver disease. Expert Rev Clin Pharmacol. 2019 Sep;12(9):859-865. [3]. Pharmacokinetic/pharmacodynamic drug-drug interactions of avatrombopag when coadministered with dual or selective CYP2C9 and CYP3A interacting drugs. Br J Clin Pharmacol. 2018;84(5):952-960.

Solubility Data

Solubility (In Vitro)

DMSO: 8.33 mg/mL (12.14 mM)

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.