Discovery of EST73502, a Dual μ-Opioid Receptor Agonist and σ 1 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 (σ R) 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 (EST73502) showed MOR agonism and σ R 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, 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 σ R antagonism may be a useful strategy for obtaining potent and safer analgesics and were the basis for the selection of as a clinical candidate for the treatment of pain.