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- Title
AKR-501 (YM477) a novel orally-active thrombopoietin receptor agonist.
- Authors
Fukushima-Shintani, Mari; Suzuki, Ken-ichi; Iwatsuki, Yoshiyuki; Abe, Masaki; Sugasawa, Keizo; Hirayama, Fukushi; Kawasaki, Tomihisa; Nakahata, Tatsutoshi
- 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.
- Subjects
THROMBOPOIETIN; BLOOD platelets; CELL receptors; MEGAKARYOCYTES; CELLS
- Publication
European Journal of Haematology, 2009, Vol 82, Issue 4, p247
- ISSN
0902-4441
- Publication type
Article
- DOI
10.1111/j.1600-0609.2008.01198.x