Pyrazolo[3,4-]pyrimidines as sigma-1 receptor ligands for the treatment of pain. Part 2: Introduction of cyclic substituents in position 4.

The replacement of acylamino by cyclic substituents in the position 4 of the pyrazolo[3,4-]pyrimidine scaffold, led to highly active sigma-1 receptor (σR) ligands. Phenyl or pyrazolyl groups were the best in terms of affinity for the σR and the 4-(1-methylpyrazol-5-yl) derivative, , was the most selective. Compound is also one of the best σR ligands ever described in terms of lipophilic ligand efficiency, which translates into a good physicochemical and ADMET profile. In addition, was identified as an antagonist of the σR in view of its potent antinociceptive profile in several pain models in mice.