The identification of orally bioavailable thrombopoietin agonists.
Recently, we disclosed a series of potent pyrimidine benzamide-based thrombopoietin receptor agonists. Unfortunately, the structural features required for the desired activity conferred physicochemical properties that were not favorable for the development of an oral agent. The physical properties of the series were improved by replacing the aminopyrimidinyl group with a piperidine-4-carboxylic acid moiety. The resulting compounds possessed favorable in vivo pharmacokinetic properties, including good bioavailability.
Munchhof
Michael J
MJ
Pfizer Global Research and Development, Groton Laboratories, MS8220-2405, Eastern Point Road, Groton, CT 06340, USA.
Antipas
Amy S
AS
Blumberg
Laura C
LC
Brissette
William H
WH
Brown
Matthew F
MF
Casavant
Jeffrey M
JM
Doty
Jonathan L
JL
Driscoll
James
J
Harris
Thomas M
TM
Wolf-Gouveia
Lilli A
LA
Jones
Christopher S
CS
Li
Qifang
Q
Linde
Robert G
RG
Lira
Paul D
PD
Marfat
Anthony
A
McElroy
Eric
E
Mitton-Fry
Mark
M
McCurdy
Sandra P
SP
Reiter
Lawrence A
LA
Ripp
Sharon L
SL
Shavnya
Andrei
A
Thomasco
Lisa M
LM
Trevena
Kristen A
KA
D000284:Administration, Oral; D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism*; D001682:Biological Availability; D018938:Caco-2 Cells; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism*; D010880:Piperidines / Q000138:chemical synthesis / Q000378:metabolism; D011718:Pyrazinamide / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000378:metabolism; D051381:Rats; D053628:Receptors, Thrombopoietin / Q000819:agonists* / Q000378:metabolism*
D001565:Benzoates; D006834:Hydrazines; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D053628:Receptors, Thrombopoietin; D011718:Pyrazinamide; C005296:pyrazinoic acid; C032727:piperidine; C030986:pyrimidine; C520809:eltrombopag