title: Pyrimidine benzamide-based thrombopoietin receptor agonists.
abstract: A series of pyrimidine benzamide-based thrombopoietin receptor agonists is described. The lead molecule contains a 2-amino-5-unsubstituted thiazole, a group that has been associated with idiosyncratic toxicity. The potential for metabolic oxidation at C-5 of the thiazole, the likely source of toxic metabolites, was removed by substitution at C-5 or by replacing the thiazole with a thiadiazole. Potency in the series was improved by modifying the substituents on the pyrimidine and/or on the thiazole or thiadiazole pendant aryl ring. In vivo examination revealed that compounds from the series are not highly bioavailable. This is attributed to low solubility and poor permeability.
authors: Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA.
authors: Lawrence A
authors: LA
authors: Reiter
authors: Chakrapani
authors: C
authors: Subramanyam
authors: Emilio J
authors: EJ
authors: Mangual
authors: Christopher S
authors: CS
authors: Jones
authors: Marc I
authors: MI
authors: Smeets
authors: William H
authors: WH
authors: Brissette
authors: Sandra P
authors: SP
authors: McCurdy
authors: Paul D
authors: PD
authors: Lira
authors: Robert G
authors: RG
authors: Linde
authors: Qifang
authors: Q
authors: Li
authors: Fangning
authors: F
authors: Zhang
authors: Amy S
authors: AS
authors: Antipas
authors: Laura C
authors: LC
authors: Blumberg
authors: Jonathan L
authors: JL
authors: Doty
authors: James P
authors: JP
authors: Driscoll
authors: Michael J
authors: MJ
authors: Munchhof
authors: Sharon L
authors: SL
authors: Ripp
authors: Andrei
authors: A
authors: Shavnya
authors: Richard M
authors: RM
authors: Shepard
authors: Diana
authors: D
authors: Sperger
authors: Lisa M
authors: LM
authors: Thomasco
authors: Kristen A
authors: KA
authors: Trevena
authors: Lilli A
authors: LA
authors: Wolf-Gouveia
authors: Liling
authors: L
authors: Zhang
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003198:Computer Simulation; D003429:Cross Reactions; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008970:Molecular Weight; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D053628:Receptors, Thrombopoietin / Q000819:agonists*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D018952:Antigens, CD34; D001549:Benzamides; D011743:Pyrimidines; D053628:Receptors, Thrombopoietin