AKR‐501 (YM477) a novel orally‐active thrombopoietin receptor agonist
- 19 February 2009
- journal article
- Published by Wiley in European Journal of Haematology
- Vol. 82 (4), 247-254
- https://doi.org/10.1111/j.1600-0609.2008.01198.x
Abstract
Thrombopoietin (TPO) is the principal physiologic regulator of platelet production. We have searched for small molecule compounds that mimic the action of TPO by using human TPO receptor-expressed in Ba/F3 cells, resulting in the discovery of AKR-501 (YM477). AKR-501 specifically targeted the TPO receptor and stimulated megakaryocytopoiesis throughout the development and maturation of megakaryocytes just as rhTPO did. AKR-501, however, was shown to be effective only in humans and chimpanzees with high species specificity. Therefore, we examined the in vivo platelet-increasing effect of AKR-501 in human platelet producing non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice transplanted with human fetal liver CD34(+) cells. Daily oral administration of AKR-501 dose-dependently increased the number of human platelets in these mice, with significance achieved at doses of 1 mg/kg and above. The peak unbound plasma concentrations of AKR-501 after administration at 1 mg/kg in NOD/SCID mice were similar to those observed following administration of an active oral dose in human subjects. These results suggest that AKR-501 is an orally-active TPO receptor agonist that may be useful in the treatment of patients with thrombocytopenia.Keywords
This publication has 21 references indexed in Scilit:
- AKR-501 (YM477) in combination with thrombopoietin enhances human megakaryocytopoiesisExperimental Hematology, 2008
- Discovery and biological evaluation of benzo[a]carbazole-based small molecule agonists of the thrombopoietin (Tpo) receptorBioorganic & Medicinal Chemistry Letters, 2008
- Optimization of small molecule agonists of the thrombopoietin (Tpo) receptor derived from a benzo[a]carbazole hit scaffoldBioorganic & Medicinal Chemistry Letters, 2008
- Molecular features crucial to the activity of pyrimidine benzamide-based thrombopoietin receptor agonistsBioorganic & Medicinal Chemistry Letters, 2008
- New thrombopoietic growth factorsBlood, 2007
- Efficient assay for evaluating human thrombopoiesis using NOD/SCID mice transplanted with cord blood CD34+ cellsEuropean Journal of Haematology, 2006
- A novel nonpeptidyl human c-Mpl activator stimulates human megakaryopoiesis and thrombopoiesisBlood, 2006
- Discovery and characterization of a selective, nonpeptidyl thrombopoietin receptor agonistExperimental Hematology, 2005
- Hematopoietic Repopulating Ability of Cord Blood CD34+Cells in NOD/Shi‐scidMiceThe International Journal of Cell Cloning, 2000
- Assay of human stem cells by repopulation of NOD/SCID miceThe International Journal of Cell Cloning, 1997