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.
Design, Synthesis, Biological Activity, and ADME Properties of Pyrazolo[3,4-d]pyrimidines Active in Hypoxic Human Leukemia Cells: A Lead Optimization Study / 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. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 54(2011), pp. 2610-2626. [10.1021/jm1012819]