Synthesis and Structure–Activity Relationship Study of a New Series of Selective σ₁ Receptor Ligands for the Treatment of Pain: 4‑Aminotriazoles

The synthesis and pharmacological activity of a new series of 4-aminotriazoles as potent σ₁ receptor (σ₁R) ligands are reported. The compounds were prepared using a 4–5-step process, involving as a key step a click chemistry reaction between ynamides and azides. The most active compounds exhibited nanomolar potency for the σ₁R, and the selectivity over the σ₂R was improved on decreasing the central amine basicity. It was concluded that in order to achieve good σ₁R potency a minimum lipophilicity was required, while limiting to a defined range of cLog<i>P</i> avoided human ether-a-go-go-related gene channel inhibition. This made the most interesting derivatives to be concentrated in a narrow margin of lipophilicity. Among them, compound <b>13g</b> exhibited the most potent in vivo antinociceptive properties, which are indicative of its antagonist character

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

Synthesis and Biological Evaluation of a New Series of Hexahydro‑2<i>H</i>‑pyrano[3,2‑<i>c</i>]quinolines as Novel Selective σ₁ Receptor Ligands

The synthesis and pharmacological activity of a new series of hexahydro-2<i>H</i>-pyrano­[3,2-<i>c</i>]­quinoline derivatives as potent σ₁ receptor (σ₁R) ligands are reported. This family, which does not contain the highly basic amino group usually present in other σ₁R ligands, showed high selectivity over the σ₂ receptor (σ₂R). The activity was shown to reside in only one of the four possible diastereoisomers, which exhibited a perfect match with known σ₁R pharmacophores. A hit to lead program based on a high-throughput screening hit (<b>8a</b>) led to the identification of compound <b>32c</b>, with substantially improved activity and physicochemical properties. Compound <b>32c</b> also exhibited a good ADMET (absorption, distribution, metabolism, excretion, toxicity) profile and was identified as a σ₁R antagonist on the basis of its analgesic activity in the mouse capsaicin and formalin models of neurogenic pain