Tricyclic Triazoles as σ₁ Receptor Antagonists for Treating Pain.

ID: ALA5096172

Journal: J Med Chem

Title: Tricyclic Triazoles as σ₁ Receptor Antagonists for Treating Pain.

Authors: Díaz JL, Cuevas F, Oliva AI, Font D, Sarmentero MÁ, Álvarez-Bercedo P, López-Valbuena JM, Pericàs MA, Enrech R, Montero A, Yeste S, Vidal-Torres A, Álvarez I, Pérez P, Cendán CM, Cobos EJ, Vela JM, Almansa C.

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 pK_a (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.

CiteXplore: 33826322

DOI: 10.1021/acs.jmedchem.1c00244

Patent ID: ┄