Pyrimidine benzamide-based thrombopoietin receptor agonists.
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.
Reiter
Lawrence A
LA
Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA.
Subramanyam
Chakrapani
C
Mangual
Emilio J
EJ
Jones
Christopher S
CS
Smeets
Marc I
MI
Brissette
William H
WH
McCurdy
Sandra P
SP
Lira
Paul D
PD
Linde
Robert G
RG
Li
Qifang
Q
Zhang
Fangning
F
Antipas
Amy S
AS
Blumberg
Laura C
LC
Doty
Jonathan L
JL
Driscoll
James P
JP
Munchhof
Michael J
MJ
Ripp
Sharon L
SL
Shavnya
Andrei
A
Shepard
Richard M
RM
Sperger
Diana
D
Thomasco
Lisa M
LM
Trevena
Kristen A
KA
Wolf-Gouveia
Lilli A
LA
Zhang
Liling
L
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
D018952:Antigens, CD34; D001549:Benzamides; D011743:Pyrimidines; D053628:Receptors, Thrombopoietin