Determination of permeability and lipophilicity of pyrazolo-pyrimidine tyrosine kinase inhibitors and correlation with biological data.

A library of 23 pyrazolo-pyrimidine compds. Src tyrosine kinase (TK) inhibitors, that reduced proliferation of a human osteogenic sarcoma cell line, was taken to investigate lack of correlation between inhibition of cellular viability (CV%) and enzymic inhibition consts. (K i Src). With the aim of understanding this behavior, we focused on physico-chem. parameters which characterize partition coeff. and diffusion through membrane. Parallel artificial membrane permeability assay (PAMPA) has been frequently used for the evaluation of in vitro permeability of new chem. entities and, in this paper, a new approach for detg. permeability of low sol. compds. was obtained. Goodness of PAMPA methodol. was confirmed by log K w and computational approaches, by VolSurf, Cerius2 and QikProp software programs. The results suggest that the lipophilicity and passive diffusion across the membranes do not significantly influence the activity of the compds. This trend can be explained by a different target for some of the compds. in our set. In fact some compds. resulted also to be active toward Abl enzyme, another cytoplasmatic TK.