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.
Abe
Masaki
M
Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. masaki.abe@jp.astellas.com
Suzuki
Ken-Ichi
K
Sakata
Chinatsu
C
Sugasawa
Keizo
K
Hirayama
Fukushi
F
Koga
Yuji
Y
Kawasaki
Tomihisa
T
Naganuma
Shin
S
Itoh
Hiroyuki
H
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