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

MedChemComm Pub Date: 2017-04-20 DOI: 10.1039/C7MD00078B

Abstract

The replacement of acylamino by cyclic substituents in the position 4 of the pyrazolo[3,4-d]pyrimidine scaffold, led to highly active sigma-1 receptor (σ1R) ligands. Phenyl or pyrazolyl groups were the best in terms of affinity for the σ1R and the 4-(1-methylpyrazol-5-yl) derivative, 12f, was the most selective. Compound 12f is also one of the best σ1R ligands ever described in terms of lipophilic ligand efficiency, which translates into a good physicochemical and ADMET profile. In addition, 12f was identified as an antagonist of the σ1R in view of its potent antinociceptive profile in several pain models in mice.

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