title: The identification of orally bioavailable thrombopoietin agonists.
abstract: 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.
authors.affiliation: Pfizer Global Research and Development, Groton Laboratories, MS8220-2405, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Munchhof
authors.forename: Amy S
authors.initials: AS
authors.lastname: Antipas
authors.forename: Laura C
authors.initials: LC
authors.lastname: Blumberg
authors.forename: William H
authors.initials: WH
authors.lastname: Brissette
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Brown
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Casavant
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Doty
authors.forename: James
authors.initials: J
authors.lastname: Driscoll
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Harris
authors.forename: Lilli A
authors.initials: LA
authors.lastname: Wolf-Gouveia
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Jones
authors.forename: Qifang
authors.initials: Q
authors.lastname: Li
authors.forename: Robert G
authors.initials: RG
authors.lastname: Linde
authors.forename: Paul D
authors.initials: PD
authors.lastname: Lira
authors.forename: Anthony
authors.initials: A
authors.lastname: Marfat
authors.forename: Eric
authors.initials: E
authors.lastname: McElroy
authors.forename: Mark
authors.initials: M
authors.lastname: Mitton-Fry
authors.forename: Sandra P
authors.initials: SP
authors.lastname: McCurdy
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Reiter
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Ripp
authors.forename: Andrei
authors.initials: A
authors.lastname: Shavnya
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Thomasco
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Trevena
mesh_terms: 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*
chemical_list: D001565:Benzoates; D006834:Hydrazines; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D053628:Receptors, Thrombopoietin; D011718:Pyrazinamide; C005296:pyrazinoic acid; C032727:piperidine; C030986:pyrimidine; C520809:eltrombopag