Synthesis and Biological Evaluation of the 1‑Arylpyrazole Class of σ₁ Receptor Antagonists: Identification of 4‑{2-[5-Methyl-1-(naphthalen-2-yl)‑1<i>H</i>‑pyrazol-3-yloxy]ethyl}morpholine (S1RA, E‑52862)

The synthesis and pharmacological activity of a new series of 1-arylpyrazoles as potent σ₁ receptor (σ₁R) antagonists are reported. The new compounds were evaluated in vitro in human σ₁R and guinea pig σ₂ receptor (σ₂R) binding assays. The nature of the pyrazole substituents was crucial for activity, and a basic amine was shown to be necessary, in accordance with known receptor pharmacophores. A wide variety of amines and spacer lengths between the amino and pyrazole groups were tolerated, but only the ethylenoxy spacer and small cyclic amines provided compounds with sufficient selectivity for σ₁R vs σ₂R. The most selective compounds were further profiled, and compound <b>28</b>, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1<i>H</i>-pyrazol-3-yloxy]­ethyl}­morpholine (S1RA, E-52862), which showed high activity in the mouse capsaicin model of neurogenic pain, emerged as the most interesting candidate. In addition, compound <b>28</b> exerted dose-dependent antinociceptive effects in several neuropathic pain models. This, together with its good physicochemical, safety, and ADME properties, led compound <b>28</b> to be selected as clinical candidate