2. Academic Validation
  3. EST64454: a Highly Soluble σ1 Receptor Antagonist Clinical Candidate for Pain Management

EST64454: a Highly Soluble σ1 Receptor Antagonist Clinical Candidate for Pain Management

  • J Med Chem. 2020 Dec 10;63(23):14979-14988. doi: 10.1021/acs.jmedchem.0c01575.
José Luis Díaz 1,  Mónica García 1,  Antoni Torrens 1,  Ana María Caamaño 2,  Juan Enjo 2,  Cristina Sicre 2,  Adriana Lorente 1,  Adriana Port 1,  Ana Montero 1,  Sandra Yeste 1,  Inés Álvarez 1,  Miquel Martín 3,  Rafael Maldonado 3,  Beatriz de la Puente 1,  Alba Vidal-Torres 1,  Cruz Miguel Cendán 4,  José Miguel Vela 1,  Carmen Almansa 1
Affiliations

Affiliations

  • 1 ESTEVE Pharmaceuticals, Torre Esteve, Passeig de la Zona Franca, 109, 08038 Barcelona, Spain.
  • 2 Galchimia, S.A., Cebreiro, s/n, 15823 O Pino, A Coruña, Spain.
  • 3 Laboratory of Neuropharmacology, Facultat de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra, Dr. Aiguader, 88, 08003 Barcelona, Spain.
  • 4 Department of Pharmacology, Faculty of Medicine, University of Granada, 18016 Granada, Spain.
PMID: 33237785 DOI: 10.1021/acs.jmedchem.0c01575
Abstract

The synthesis and pharmacological activity of a new series of pyrazoles that led to the identification of 1-(4-(2-((1-(3,4-difluorophenyl)-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethanone (9k, EST64454) as a σ1 receptor (σ1R) antagonist clinical candidate for the treatment of pain are reported. The compound 9k is easily obtained through a five-step synthesis suitable for the production scale and shows an outstanding aqueous solubility, which together with its high permeability in Caco-2 cells will allow its classification as a BCS class I compound. It also shows high metabolic stability in all species, linked to an adequate pharmacokinetic profile in rodents, and antinociceptive properties in the capsaicin and partial sciatic nerve ligation models in mice.

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