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

Article Details

Citation

Copy to clipboard

Radi M, Dreassi E, Brullo C, Crespan E, Tintori C, Bernardo V, Valoti M, Zamperini C, Daigl H, Musumeci F, Carraro F, Naldini A, Filippi I, Maga G, Schenone S, Botta M

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

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

PubMed ID

21443205 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Imatinib	Tyrosine-protein kinase ABL1	Ki (nM)	13	N/A	N/A	Details