Tricyclic Triazoles as σ₁ Receptor Antagonists for Treating Pain

Abstract

The synthesis and pharmacological activity of a new series of 5a,7,8,8a-tetrahydro-4<i>H</i>,6<i>H</i>-pyrrolo[3,4-<i>b</i>][1,2,3]triazolo[1,5-<i>d</i>][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 p<i>K</i>_a (around 5) that correlates with high exposure levels in rodents. Two compounds displaying a differential brain-to-plasma ratio distribution profile, <b>12lR</b> and <b>12qS</b>, exhibited a good analgesic profile and were selected as preclinical candidates for the treatment of pain.