ESTEVE Pharmaceuticals, Torre Esteve, Passeig de la Zona Franca, 109, 08038 Barcelona, Spain.
Galchimia, S.A., Cebreiro, s/n, 15823 O Pino, A Coruña, Spain.
J Med Chem. 2020 Dec 10;63(23):14979-14988. doi: 10.1021/acs.jmedchem.0c01575. Epub 2020 Nov 25.
The synthesis and pharmacological activity of a new series of pyrazoles that led to the identification of 1-(4-(2-((1-(3,4-difluorophenyl)-1-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethanone (, EST64454) as a σ receptor (σR) antagonist clinical candidate for the treatment of pain are reported. The compound 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.
报告了一系列新的吡唑类化合物的合成和药理学活性，这些化合物导致了 1-(4-(2-((1-(3,4-二氟苯基)-1-吡唑-3-基)甲氧基)乙基)哌嗪-1-基)乙酮（，EST64454）的鉴定，它是一种 σ 受体（σR）拮抗剂临床候选药物，用于治疗疼痛。该化合物可通过适合生产规模的五步法合成轻松获得，具有出色的水溶性，加上其在 Caco-2 细胞中的高渗透性，将使其被归类为 BCS 类 I 化合物。它在所有物种中也表现出高代谢稳定性，与啮齿动物中适当的药代动力学特征相关，并具有辣椒素和部分坐骨神经结扎模型中小鼠的镇痛特性。
