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J Med Chem. 2011 Apr 28;54(8):2610-26. doi: 10.1021/jm1012819. Epub 2011 Mar 28.

Design, synthesis, biological activity, and ADME properties of pyrazolo[3,4-d]pyrimidines active in hypoxic human leukemia cells: a lead optimization study.

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Dipartimento Farmaco Chimico Tecnologico, University of Siena, Siena, Italy.


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.

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