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Title: Design, synthesis, biological activity and ADME properties of pyrazolo[3,4-d]pyrimidines active in hypoxic human leukemia cells: a lead optimization study
Authors: Radi, Marco
Dreassi, Elena 
C., Brullo
E., Crespan
Tintori, Cristina
V., Bernardo
Valoti, Massimo
Zamperini, Claudio
H., Daigl
F., Musumeci
Carraro, Fabio
Naldini, Antonella
Filippi, Irene
G., Maga
S., Schenone
Botta, Maurizio 
Issue Date: 2011
Project: None 
A family of dual Src/Abl inhibitors characterized by a substituted pyrazolo[3,4-d]pyrimidine scaffold was previously reported by us and proved to be active against several tumor cell lines. Among these compounds, a promising antileukemia lead (1) has been recently identified, but, unfortunately, it suffers from substandard pharmaceutical properties. Accordingly, an approach for the optimization of the lead 1 is described in the present work. A series of more soluble pyrazolo[3,4-d]pyrimidine derivatives were rationally designed and proved to maintain the dual Src/Abl activity of the lead. Selected compounds showed an interesting activity profile against three different leukemic cells also in hypoxic conditions, which are usually characterized by imatinib-resistance. Finally, in vitro ADME properties (PAMPA permeation, water solubility, microsomal stability) for the most promising inhibitors were also evaluated, thus allowing the identification of a few optimized analogues of lead 1 as promising antileukemia agents.
ISSN: 0022-2623
DOI: 10.1021/jm1012819
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