Tricyclic Triazoles as σ 1 Receptor Antagonists for Treating Pain
The synthesis and pharmacological activity of a new series of 5a,7,8,8a-tetrahydro-4H,6H-pyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine derivatives as potent sigma-1 receptor (σ1R) ligands are reported. A lead optimization program aimed at improving the aqueous solubility of parent racemic nonpolar derivatives led to the identification of several σ1R antagonists with a good absorption, distribution, metabolism, and excretion in vitro profile, no off-target affinities, and characterized by a low basic pKa (around 5) that correlates with high exposure levels in rodents. Two compounds displaying a differential brain-to-plasma ratio distribution profile, 12lR and 12qS, exhibited a good analgesic profile and were selected as preclinical candidates for the treatment of pain.
Díaz, J. L.; Cuevas, F.; Oliva, A. I.; Font, D.; Sarmentero, M. A.; Álvarez-Bercedo, P.;López-Valbuena, J. M.; Pericàs, M. A.; Enrech, R.; Montero, A.; Yeste, S.; Vidal-Torres, A.; Álvarez, I.; Pérez, P.; Miguel Cendán, C.; Cobos, E. J.; Vela, J. M.; Almansa, C.
J Med Chem. 2021, 64 (8), 5157-5170
DOI:
10.1021/acs.jmedchem.1c00244
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