학술논문
Tricyclic Triazoles as σ1Receptor Antagonists for Treating Pain
Document Type
Article
Author
Díaz, José Luis; Cuevas, Félix; Oliva, Ana I.; Font, Daniel; Sarmentero, M. Ángeles; Álvarez-Bercedo, Paula; López-Valbuena, José M.; Pericàs, Miquel A.; Enrech, Raquel; Montero, Ana; Yeste, Sandra; Vidal-Torres, Alba; Álvarez, Inés; Pérez, Pilar; Cendán, Cruz Miguel; Cobos, Enrique J.; Vela, José Miguel; Almansa, Carmen
Source
Journal of Medicinal Chemistry; 20210101, Issue: Preprints
Subject
Language
ISSN
00222623; 15204804
Abstract
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, 12lRand 12qS, exhibited a good analgesic profile and were selected as preclinical candidates for the treatment of pain.