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.

Radi, M., Dreassi, E., C., B., E., C., Tintori, C., V., B., et al. (2011). Design, synthesis, biological activity and ADME properties of pyrazolo[3,4-d]pyrimidines active in hypoxic human leukemia cells: a lead optimization study. JOURNAL OF MEDICINAL CHEMISTRY, 54, 2610-2626 [10.1021/jm1012819].

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

RADI, MARCO;DREASSI, ELENA;TINTORI, CRISTINA;VALOTI, MASSIMO;ZAMPERINI, CLAUDIO;CARRARO, FABIO;NALDINI, ANTONELLA;FILIPPI, IRENE;BOTTA, MAURIZIO
2011-01-01

Abstract

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.
Radi, M., Dreassi, E., C., B., E., C., Tintori, C., V., B., et al. (2011). Design, synthesis, biological activity and ADME properties of pyrazolo[3,4-d]pyrimidines active in hypoxic human leukemia cells: a lead optimization study. JOURNAL OF MEDICINAL CHEMISTRY, 54, 2610-2626 [10.1021/jm1012819].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/20266
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