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.
A new series of propionamide derivatives was developed as dual μ-opioid receptor agonists and σ 1 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, 18g, 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.
EST64454 is a selective sigma-1 receptor ligand intended for orally administered pain treatment that showed a promising profile in the lead optimization process. As part of the preliminary compound profiling, the potential for future drug-drug interactions was explored in vitro. Both direct and time-dependent CYP inhibition for CYP1A2, 2C9, 2C19, 2D6 and 3A4 was studied in human liver microsomes. EST64454 showed a low potential for CYP inhibition (IC 50 between 100 and 1000 µM) and as time-dependent inhibitor (IC 50 shift mainly around 1). CYP induction studies with HepaRG cells revealed no CYP induction at concentrations ≤50 µM, as shown by the CYP1A2, 3A4 and 2B6 activities measured. Reaction phenotyping was assessed after incubation with recombinant human enzymes. Although a very low metabolism was observed, several enzymes catalyzed the formation of metabolites, including CYP3A4, 2C19 and flavin monooxygenases (FMO) 1 and 3. EST64454 was not a P-glycoprotein (P-gp) substrate and was highly permeable in Caco-2 cells. P-gp inhibition was only observed at 200 µM, the highest concentration studied. Preliminary studies suggest that neither CYP nor P-gp interaction of EST64454 would be of any concern for further development. At later stages, the interaction kinetics and the clinical relevance of these findings will be thoroughly evaluated.
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