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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• 作者：Marco Radi ; Elena Dreassi ; Chiara Brullo ; Emmanuele Crespan ; Cristina Tintori ; Vincenzo Bernardo ; Massimo Valoti ; Claudio Zamperini ; Henry Daigl ; Francesca Musumeci ; Fabio Carraro ; Antonella Naldini ; Irene Filippi ; Giovanni Maga ; Silvia Schenone ; Maurizio Botta
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 28, 2011
• 年：2011
• 卷：54
• 期：8
• 页码：2610-2626
• 全文大小：1481K
• 年卷期：v.54,no.8(April 28, 2011)
• ISSN：1520-4804

文摘

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.