title: AKR-501 (YM477) a novel orally-active thrombopoietin receptor agonist.
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.
authors.affiliation: QA, RA and Pharmacovigilance, Astellas Pharma Inc, Tokyo, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Fukushima-Shintani
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Iwatsuki
authors.forename: Masaki
authors.initials: M
authors.lastname: Abe
authors.forename: Keizo
authors.initials: K
authors.lastname: Sugasawa
authors.forename: Fukushi
authors.initials: F
authors.lastname: Hirayama
authors.forename: Tomihisa
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Tatsutoshi
authors.initials: T
authors.lastname: Nakahata
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018952:Antigens, CD34 / Q000502:physiology; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation; D005312:Fetal Blood / Q000166:cytology; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008099:Liver / Q000196:embryology; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D002679:Pan troglodytes; D010976:Platelet Count; D011003:Ploidies; D011123:Polyploidy; D053628:Receptors, Thrombopoietin / Q000819:agonists* / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D033581:Stem Cell Transplantation; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*; D013926:Thrombopoietin / Q000235:genetics / Q000494:pharmacology
chemical_list: D018952:Antigens, CD34; D053628:Receptors, Thrombopoietin; D011994:Recombinant Proteins; D013844:Thiazoles; D013876:Thiophenes; C533238:avatrombopag; D013926:Thrombopoietin