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 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.

Fentanyl Structure as a Scaffold for Opioid/Non-Opioid Multitarget Analgesics

“…A very successful med-chem programme focused on dual µOR agonists/σ 1 R antagonists was recently described by García et al (of ESTEVE Pharmaceuticals SA) [111,112].…”

“…The initial compounds were designed as a result of merging 3D-pharmacophore models of both receptors (based on morphine for µOR and based on a model by Laggner et al [113] as well as on the in-house SAR data [114] in the case of σ 1 R). S5 for structures and affinities) were reported to have been obtained and tested [111,112], out of which about a half exhibited K i < 100 nM for MOR and about 50 of them showed K i < 100 nM for σ 1 R. Many examples had singledigit nanomolar K i 's either for one of the receptors or for both. The issues that were mainly fought with during the SAR exploration was the propensity of these structures to interact with hERG channels and α 1A -adrenergic receptors (α 1A R; associated with cardiac toxicity).…”

“…A very successful med-chem programme focused on dual μOR agonists/σ 1 R antagonists was recently described by García et al (of ESTEVE Pharmaceuticals SA) [ 111 , 112 ]. In their contributions the team disclosed 1-oxa-4,9-diazaspiro[5.5]undecane ( Figure 10 ) derivatives with the desired dual activity.…”

Multi-Target Directed Ligands (MTDLs) Binding the σ1 Receptor as Promising Therapeutics: State of the Art and Perspectives

“…Based on this model, several compounds were synthesized, and the 4-aryl-1-oxa-4,9diazaspiro [5.5]undecane derivative 13 (Figure 13) provided the best results on both targets. (13)(14)(15)(16) and their K i and IC 50 values for σ 1 (σ 1 R), µ-opioid (MOR) and alpha-1 adrenergic (α 1 AR) receptors and human ether-a-go-go-related gene channel (hERG) [139,140].…”

“…For these reasons, compound 16 was successfully tested in the paw pressure test and in the partial sciatic nerve ligation (PSNL) model in CD1 male mice. Thus, compound 16 was selected as a Phase 1 clinical candidate in the treatment of pain [140].…”