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.
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Authors | Mari Fukushima-Shintani, Ken-ichi Suzuki, Yoshiyuki Iwatsuki, Masaki Abe, Keizo Sugasawa, Fukushi Hirayama, Tomihisa Kawasaki, Tatsutoshi Nakahata |
Journal | European journal of haematology
(Eur J Haematol)
Vol. 82
Issue 4
Pg. 247-54
(Apr 2009)
ISSN: 1600-0609 [Electronic] England |
PMID | 19183407
(Publication Type: Journal Article)
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Chemical References |
- Antigens, CD34
- Receptors, Thrombopoietin
- Recombinant Proteins
- Thiazoles
- Thiophenes
- avatrombopag
- Thrombopoietin
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Topics |
- Administration, Oral
- Animals
- Antigens, CD34
(physiology)
- Blood Platelets
(cytology, drug effects, physiology)
- Cell Differentiation
- Fetal Blood
(cytology)
- Hematopoiesis
(drug effects, physiology)
- Humans
- Liver
(embryology)
- Megakaryocytes
(cytology, drug effects, physiology)
- Mice
- Mice, Inbred NOD
- Mice, SCID
- Pan troglodytes
- Platelet Count
- Ploidies
- Polyploidy
- Receptors, Thrombopoietin
(agonists, genetics, physiology)
- Recombinant Proteins
(pharmacology)
- Stem Cell Transplantation
- Thiazoles
(administration & dosage, pharmacology)
- Thiophenes
(administration & dosage, pharmacology)
- Thrombopoietin
(genetics, pharmacology)
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