AKR-501 (YM477) a novel orally-active thrombopoietin receptor agonist

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.