Avatrombopag

Inquiry

Cat Number

API570406983

CAS Number

570406-98-3

If you have any other questions, please contact our experts.

Product Detail Description Scientific Support Customer Q&A

CAS Number

570406-98-3

Storage

Store at -20℃

Synonyms

AKR-501; E5501; YM477; 1-[3-chloro-5-({[4-(4-chloro-2-thienyl)-5-(4-cyclohexyl-1-piperazinyl)-1,3-thiazol-2-yl]amino}carbonyl)-2-pyridinyl]-4-piperidinecarboxylic acid; 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl)carbamoyl)pyridin-2-yl)piperidine-4-carboxylic acid

Molecular Formula

C29H34Cl2N6O3S2

Molecular Weight

649.7

Smiles

ClC1=CC(C(NC2=NC(C3=CC(Cl)=CS3)=C(N4CCN(C5CCCCC5)CC4)S2)=O)=CN=C1N6CCC(C(O)=O)CC6

Appearance

White to off-white solid

General Description

Avatrombopag is a small-molecule, non-peptide, oral, thrombopoietin receptor agonist with a chemical structure that is highly selective for its target. On a molecular scale, avatrombopag is defined by a thiazole-dicarboxamide scaffold covalently bound to various aromatic ring systems, such as chlorophenyl and pyridyl rings. The specific spatial arrangement of these chemical moieties allows it to allosterically bind to the transmembrane domain of the TPO receptor. Avatrombopag does not, on a molecular level, compete with endogenous TPO for the same binding site; this is one reason that avatrombopag's biological activity does not produce direct competitive inhibition against endogenous thrombopoietin.

Mechanism of Action

Avatrombopag is an orally administered agonist of the thrombopoietin receptor (TPOR) that stimulates megakaryopoiesis. By binding to and activating TPOR—a cytokine receptor in the hematopoietin superfamily—avatrombopag promotes the proliferation and differentiation of bone marrow progenitor cells into megakaryocytes. This mechanism boosts platelet production and may mitigate chemotherapy-induced thrombocytopenia (CIT).

Application

Avatrombopag is an orally administered second generation thrombopoietin receptor agonist (TPO-RA) approved for the treatment of primary chronic immune thrombocytopenia (ITP) in adult patients who are refractory to or have an unsatisfactory response to other treatments and for the treatment of thrombocytopenia in adult patients with chronic liver disease (CLD) who are scheduled to undergo an invasive procedure.

Avatrombopag is a thrombopoietin receptor agonist (TPO mimetic) which structurally resembles the endogenous ligand thrombopoietin (TPO), the key natural growth factor that regulates platelet production. Avatrombopag binds to the TPO receptor on a different site to TPO to activate downstream JAK/STAT and MAPK (ERK) signaling pathways that drive megakaryocyte proliferation and differentiation. In vitro, avatrombopag triggers concentration-dependent proliferation of TPO receptor-expressing cells (EC50 3.3 nmol/L) and megakaryocyte differentiation from CD34+ cells (EC50 25.0 nmol/L) with equivalent potency to recombinant human TPO. The compound also has additive effects with rhTPO on megakaryocyte proliferation and early progenitor cell maturation. In mouse models, avatrombopag dose-dependently increases human platelet counts in vivo. Importantly, avatrombopag increases platelet count in chronic liver disease patients, and there is no evidence of increased platelet activation and reactivity with avatrombopag treatment, in contrast to what has been hypothesized as a property of TPO to lower activation thresholds. The differential binding to the TPO receptor by avatrombopag does not impede the function of endogenous TPO.

Fig. 1 Mechanism of action of avatrombopag. (Markham A. 2021)