Discovery of EST73502, a Dual µ-Opioid Receptor Agonist and σ1 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 σ1 receptor (σ1R) 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. Compound 14u (EST73502) showed MOR agonism and σ1R antagonism and a potent analgesic activity, comparable to the MOR agonist oxycodone in animal models of acute and chronic pain after single and repeated administration. Contrary to oxycodone, 14u produces analgesic activity with reduced opioid-induced relevant adverse events, like intestinal transit inhibition and naloxone-precipitated behavioral signs of opiate withdrawal. These results provide evidence that dual MOR agonism and σ1R antagonism may be a useful strategy for obtaining potent and safer analgesics and were the basis for the selection of 14u as a clinical candidate for the treatment of pain.

Synthesis and structure-activity relationship study of a new series of selective σ(1) 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 cLogP 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 13g exhibited the most potent in vivo antinociceptive properties, which are indicative of its antagonist character.

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. A hit to lead program based on a high-throughput screening hit (8a) led to the identification of compound 32c, with substantially improved activity and physicochemical properties. Compound 32c 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.

Solid-phase synthesis of a combinatorial library of dihydroceramide analogues and its activity in human alveolar epithelial cells.

Solid-phase synthesis of a small combinatorial library of dihydroceramide analogues as mixtures of erythro and threo diastereomers is described. Some dihydroceramide analogues cause growth arrest and apoptosis in a dose-dependent manner in human alveolar epithelial cells. This activity is likely due to the threo isomers, as evidenced by cellular studies with a pair of diastereomerically pure N-acyldihydrosphingosines. The apoptotic activity reported in this work provides information for the design of new compounds that may provide the basis for the generation of biochemical tools for the study of different pathologies where ceramide and/or dihydroceramide are involved.

2-Methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles: versatile starting materials for the synthesis of libraries with diverse heterocyclic scaffolds.

Heterocyclic demonstration libraries for agrochemical screening were prepared from the common intermediates 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles (1), using standard solution-phase techniques. A total of 18 screening libraries were prepared in good to excellent yields. Several members of these libraries were active in the first level of agrochemical screening, especially in the fungicide screen.