Discovery of EST73502, a Dual μ-Opioid Receptor Agonist and σ₁ Receptor Antagonist Clinical Candidate for the Treatment of Pain

Abstract

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 <b>14u</b> (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, <b>14u</b> 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 <b>14u</b> as a clinical candidate for the treatment of pain.