WLB-87848, a Selective σ Receptor Agonist, with an Unusually Positioned NH Group as Positive Ionizable Moiety and Showing Neuroprotective Activity.

The synthesis and pharmacological activity of a new series of thieno[2,3-]pyrimidin-4(3)-one derivatives as sigma-1 receptor (σR) ligands are reported. A hit from a high-throughput screening program was evolved into a highly potent and selective σR agonist () that contains a free NH group as positive ionizable moiety, not fulfilling the usual pharmacophoric features of the σR. The compound shows good physicochemical and ADMET characteristics, displays an agonist profile in the binding immunoglobulin protein/σR association assay, induces neuron viability in an in vitro model of β-amyloid peptide intoxication, and presents positive results against recognition memory impairment induced by hippocampal injection of Aβ peptide in rats after oral treatment, altogether making (WLB-87848) an interesting candidate for neuroprotection.

Discovery of WLB-89462, a New Drug-like and Highly Selective σ Receptor Ligand with Neuroprotective Properties.

The synthesis and pharmacological activity of a new series of isoxazolylpyrimidines as sigma-2 receptor (σR) ligands are reported. Modification of a new hit retrieved in an HTS campaign allowed the identification of the compound WLB-89462 () with good σR affinity ( = 13 nM) and high selectivity vs both the σR ( = 1777 nM) and a general panel of 180 targets. It represents one of the first σR ligands with drug-like properties, linked to a good physicochemical and ADMET profile (good solubility, no CYP inhibition, good metabolic stability, high permeability, brain penetration, and high oral exposure in rodents).

Propionamide Derivatives as Dual μ-Opioid Receptor Agonists and σ Receptor Antagonists for the Treatment of Pain.

A new series of propionamide derivatives was developed as dual μ-opioid receptor agonists and σ receptor antagonists. Modification of a high-throughput screening hit originated a series of piperazinylcycloalkylmethyl propionamides, which were explored to overcome the challenge of achieving balanced dual activity and convenient drug-like properties. The lead compound identified, , showed good analgesic effects in several animal models of both acute (paw pressure) and chronic (partial sciatic nerve ligation) pain, with reduced gastrointestinal effects in comparison with oxycodone.

Discovery of EST73502, a Dual μ-Opioid Receptor Agonist and σ Receptor Antagonist Clinical Candidate for the Treatment of Pain.

The synthesis and pharmacological activity of a new series of 4-alkyl-1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the σ receptor (σR) and the μ-opioid receptor (MOR) are reported. A lead optimization program over the initial 4-aryl analogues provided 4-alkyl derivatives with the desired functionality and good selectivity and ADME profiles.

Critical comparison of shake-flask, potentiometric and chromatographic methods for lipophilicity evaluation (log P) of neutral, acidic, basic, amphoteric, and zwitterionic drugs.

In the present study three different procedures have been compared for the determination of the lipophilicity of the unionized species (log P) of neutral, acidic, basic, amphoteric, and zwitterionic drugs. Shake-flask, potentiometric and chromatographic approaches have been assayed in a set of 66 representative compounds in different phases of advanced development. An excellent equivalence has been found between log P values obtained by shake-flask and potentiometry, while the chromatographic approach is less accurate but very convenient for screening purposes when a high-throughput is required.

Pyrazolo[3,4-]pyrimidines as sigma-1 receptor ligands for the treatment of pain. Part 2: Introduction of cyclic substituents in position 4.

The replacement of acylamino by cyclic substituents in the position 4 of the pyrazolo[3,4-]pyrimidine scaffold, led to highly active sigma-1 receptor (σR) ligands. Phenyl or pyrazolyl groups were the best in terms of affinity for the σR and the 4-(1-methylpyrazol-5-yl) derivative, , was the most selective. Compound is also one of the best σR ligands ever described in terms of lipophilic ligand efficiency, which translates into a good physicochemical and ADMET profile.

Synthesis and biological evaluation of a new series of hexahydro-2H-pyrano[3,2-c]quinolines as novel selective σ1 receptor ligands.

The synthesis and pharmacological activity of a new series of hexahydro-2H-pyrano[3,2-c]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.