WELAB BARCELONA

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

Dear colleagues, collaborators, and friends,

After more than 30 years of shared endeavours, in which we have grown personally and professionally, and with our emotions on the surface, we announce the closure of our company. We have travelled together through ups and downs, celebrated successes and overcome challenges as a team.

We extend our deepest gratitude to each of you for your dedication, passion, and commitment to a shared goal: discovering new treatments for the benefit and well-being of patients.

As we bid farewell, let’s cherish the memories we’ve created, the bonds we’ve formed, and the impact we’ve made together. Though our paths may diverge, the spirit of collaboration and camaraderie that defines our community will always endure.

We leave proud of the work accomplished and thank you for being an integral part of our journey, wishing you success in all your future challenges.

With heartfelt appreciation,

Welab’s team

We are proud to announce that Welab is partner of this new EU funded project.

In collaboration with 12 partners from 6 countries, Welab Barcelona is establishing the Antivirus Pandemic Preparedness EuropeAn pLatform (APPEAL), a European research initiative aimed at enhancing preparedness for future pandemics. This EU funded collaboration will establish a comprehensive program for the development of broad-spectrum antiviral drugs within a five year time frame ensuring drug affordability and accessibility to low income countries.
Link to the press release: https://lnkd.in/d-jmV2CS