EST64454: a Highly Soluble σ 1 Receptor Antagonist Clinical Candidate for Pain Management


Journal of Medicinal Chemistry


José Luis Díaz, Mónica García, Mónica García, Antoni Torrens, Ana María Caamaño, Juan Enjo, Cristina Sicre, Adriana Lorente, Adriana Port, Ana Montero, Sandra Yeste, Inés Álvarez, Miquel Martín, Rafael Maldonado, Beatriz de laPuente, Alba Vidal-Torres, Cruz Miguel Cendán, José Miguel Vela, and Carmen Almansa



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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