Thiophene Bioisosteres of Spirocyclic σ Receptor Ligands: Relationships between Substitution Pattern and σ Receptor Affinity

On the basis of the 6′,7′-dihydrospiro­[piperidine-4,4′-thieno­[3,2-<i>c</i>]­pyran] framework, a series of more than 30 σ ligands with versatile substituents in 1-, 2′-, and 6′-position has been synthesized and pharmacologically evaluated in order to find novel structure–affinity relationships. It was found that a cyclohexylmethyl residue at the piperidine <i>N</i>-atom instead of a benzyl moiety led to increased σ₂ affinity and therefore to decreased σ₁/σ₂ selectivity. Small substituents (e.g., OH, OCH₃, CN, CH₂OH) in 6′-position adjacent to the O-atom were well tolerated by the σ₁ receptor. Removal of the substituent in 6′-position resulted in very potent but unselective σ ligands (<b>13</b>). A broad range of substituents with various lipophilic and <i>H</i>-bond forming properties was introduced in 2′-position adjacent to the <i>S</i>-atom without loss of σ₁ affinity. However, very polar and basic substituents in both 2′- and 6′-position decreased the σ₁ affinity considerably. It is postulated that the electron density of the thiophene moiety has a big impact on the σ₁ affinity

Lead Development of Thiazolyl­sulfonamides with Carbonic Anhydrase Inhibitory Action

A series of congeners structurally related to pritelivir, <i>N</i>-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-<i>N</i>-methyl-2-[4-(2-pyridinyl)­phenyl]­acetamide, a helicase-primase inhibitor for the treatment of herpes simplex virus infections, was prepared. The synthesized primary and secondary sulfonamides were investigated as inhibitors of six physiologically and pharmacologically relevant human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, the cytosolic enzymes hCA I and II, the mitochondrial ones hCA VA and VB, and the transmembrane, tumor associated hCA IX and XII. Low nanomolar inhibition <i>K</i>_I values were detected for all of them, with a very interesting and well-defined structure–activity relationship. As many CAs are involved in serious pathologies, among which are cancer, obesity, epilepsy, glaucoma, etc., sulfonamide inhibitors as those reported here may be of interest as drug candidates. Furthermore, pritelivir itself is an effective inhibitor of some CAs, also inhibiting whole blood enzymes from several mammalian species, which may be a favorable pharmacokinetic feature of the drug which can be transported throughout the body bound to blood CA I and II

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