Identification of EST64454

EST64454 was obtained as result of a backup program aimed at improving the profile of E-52862, a Sigma-1 receptor (σ1R) antagonist in Phase II clinical trials for the treatment of pain. EST64454 is a BCS class I compound with an outstanding aqueous solubility and high permeability in Caco-2 cells. It also shows a good ADMET profile with high metabolic stability in all species, including human microsomes and hepatocytes, and an adequate pharmacokinetic profile in rodents.1,2

We explored the variation in the morpholine-containing chain of E-52862 by elongation of the distance of the O-atom to the pyrazole ring. Suboptimal aqueous solubility of E-52862 was improved by reducing lipophilicity while maintaining good affinity, a challenging task because polar groups are poorly tolerated in the highly hydrophobic σ1R. EST64454 complies with the central nervous system multiparameter optimization (CNS MPO) algorithm, resulting beneficial for the improvement of the overall safety profile as the compound:

  • is devoid of potential for drug-drug interactions based on both direct and time-dependent CYP inhibition.
  • shows a good in vitro safety profile with lack of cytotoxic and genotoxic potential and no hERG inhibition at 10 mM.
  • does not show any significant affinity for another 180 molecular targets, indicating that the relevant in vivo activity observed is only due to σ1R binding.

In addition, a route was developed for its large-scale production without the need of chromatographic purification throughout the whole process and using easily available, nontoxic starting materials ·3


1.Díaz JL et al J. Med. Chem, 2020, 63, 14979-14988.

2.García, M et al WO2011147910A1, Dec 1, 2011.

3.Almansa C et al WO2018109082A1, Jun 21, 2018