Pharmacological profile of AS1670542, a novel orally-active human thrombopoietin receptor agonist.
Eltrombopag, an orally-active small molecule thrombopoietin (TPO) receptor agonist, was used for the first time in 2008 to treat patients with chronic idiopathic thrombocytopenic purpura. Here, we investigated the pharmacological effect of a new orally-active small molecule TPO receptor agonist which may be effective in treating these patients. 50% effective concentration values for cell proliferation with AS1670542 or eltrombopag were 1.9 and 13nM, respectively, while those for megakaryocyte colony formation from human cord blood CD34(+) cells with AS1670542 or eltrombopag were 260 and 950nM, respectively. On Day 14 after the start of administration, AS1670542 significantly increased the number of human platelets in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice with transplanted human hematopoietic stem cells at 0.3 (P<0.05); in contrast, while administration of eltrombopag also increased the numbers of these platelets at 30mg/kg/day (P=0.058), no statistical significance was noted in the increase. Here, we identified AS1670542, a novel orally-active TPO receptor agonist which mimics the biological activity of TPO and may demonstrate greater in vitro and in vivo pharmacologically efficacy than eltrombopag.
Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. masaki.abe@jp.astellas.com
Masaki
M
Abe
Ken-Ichi
K
Suzuki
Chinatsu
C
Sakata
Keizo
K
Sugasawa
Fukushi
F
Hirayama
Yuji
Y
Koga
Tomihisa
T
Kawasaki
Shin
S
Naganuma
Hiroyuki
H
Itoh
D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001565:Benzoates / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004285:Dogs; D005260:Female; D006639:Histidine / Q000378:metabolism; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010976:Platelet Count; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D053628:Receptors, Thrombopoietin / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013045:Species Specificity; D033581:Stem Cell Transplantation; D013844:Thiazoles / Q000008:administration & dosage* / Q000494:pharmacology*; D013876:Thiophenes / Q000008:administration & dosage* / Q000494:pharmacology*
D018952:Antigens, CD34; D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; D013844:Thiazoles; D013876:Thiophenes; C533238:avatrombopag; D006639:Histidine; C520809:eltrombopag