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
  • 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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