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

Abstract

The synthesis and pharmacological activity of a new series of 1-arylpyrazoles as potent σ(1) receptor (σ(1)R) antagonists are reported. The new compounds were evaluated in vitro in human σ(1)R and guinea pig σ(2) receptor (σ(2)R) 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 σ(1)R vs σ(2)R. The most selective compounds were further profiled, and compound 28, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-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 28 exerted dose-dependent antinociceptive effects in several neuropathic pain models. This, together with its good physicochemical, safety, and ADME properties, led compound 28 to be selected as clinical candidate.

Synthesis and pharmacological evaluation of like- and unlike-configured tetrahydro-2-benzazepines with the α-substituted benzyl moiety in the 5-position

“…Pale yellow oil, yield 51 mg (86%). C 21 A signal for the carbon atom C-5 is not seen in the 13 C NMR spectrum.…”

A Review of the Human Sigma-1 Receptor Structure

“…3.4). The pharmacophore models have been developed from analyses of known S1R ligands as well as binding affinity measurements of systematically substituted panels of ligands [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50]. The first pharmacophore models developed after separation of the S1R binding site from the Sigma 2 Receptor binding site [51,52] were based on disubstituted piperidines [36] and N-substituted phenylalkylamines [37].…”

Investigational sigma-1 receptor antagonists for the treatment of pain

“…The leading compound in the field and the only being developed for the treatment of pain is the pyrazole derivative S1RA (E-52862, 32, Figure 3), identified in a medicinal chemistry program as a highly active and selective s 1 R antagonist [22,98]. It was safe, well-tolerated and showed good pharmacokinetic profile following oral administration to human volunteers in Phase I studies [99] and it is currently undergoing Phase II clinical trials for the treatment of different pain states.…”

“…In Phase I studies, E-52862 exhibited good safety, tolerability and pharmacokinetic properties after single (5 --800 mg) or multiple (50 --400 mg  8 days) oral doses [98]. The results from the currently undergoing Phase II clinical trials in several neuropathic pain conditions are eagerly awaited.…”