Preliminary approach to evaluate the drug-drug interaction potential of EST73502, a dual µ-opioid receptor partial agonist and σ1 receptor antagonist.

The potential for drug-drug interactions (DDI) of EST73502 was preliminary explored . EST73502 is a new chemical entity intended for oral pain treatment with dual sigma-1 receptor (σR) antagonism and μ-opioid receptor (MOR) partial agonism, that presents a promising potent analgesic activity.Several enzymes were involved in EST73502 metabolism catalysing the formation of different metabolites, CYP3A4 and CYP2D6 being the main ones.

Preliminary assessment of pharmacokinetic drug-drug interactions of EST64401 and EST64514, two sigma-1 receptor antagonists.

EST64401 and EST64514 are two selective sigma-1 receptor ligands that showed a good profile in a lead optimization process for oral pain treatment. Their potential for pharmacokinetic-based drug-drug interactions was assessed to anticipate clinical interactions.Both compounds showed a low potential for CYP inhibition with percentages of inhibition <50% at 1 µM in recombinant human CYPs (CYP1A2, 2C9, 2C19, 2D6 and 3A4) and IC ≥75 µM for CYP3A4 and 2D6 in human liver microsomes.

Preliminary in Vitro Assessment of the Potential of EST64454, a Sigma-1 Receptor Antagonist, for Pharmacokinetic Drug-Drug Interactions.

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.

Pyrazolo[3,4-]pyrimidines as sigma-1 receptor ligands for the treatment of pain. Part 2: Introduction of cyclic substituents in position 4.

The replacement of acylamino by cyclic substituents in the position 4 of the pyrazolo[3,4-]pyrimidine scaffold, led to highly active sigma-1 receptor (σR) ligands. Phenyl or pyrazolyl groups were the best in terms of affinity for the σR and the 4-(1-methylpyrazol-5-yl) derivative, , was the most selective. Compound is also one of the best σR ligands ever described in terms of lipophilic ligand efficiency, which translates into a good physicochemical and ADMET profile.