EST64454: a Highly Soluble σ1 Receptor Antagonist Clinical Candidate for Pain Management,Journal of Medicinal Chemistry

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EST64454: a Highly Soluble σ1 Receptor Antagonist Clinical Candidate for Pain Management
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-11-25 , 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

Affiliation

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.

中文翻译：

EST64454：一种高度可溶的 σ1 受体拮抗剂，用于疼痛管理的临床候选药物

一系列新吡唑的合成和药理活性，从而鉴定出 1-(4-(2-((1-(3,4-二氟苯基)-1 H-吡唑-3-基)甲氧基)乙基)据报道，哌嗪-1-基)乙酮 ( 9k ， EST64454) 作为 σ ₁受体 (σ ₁ R) 拮抗剂临床候选药物用于治疗疼痛。化合物9k可以通过适合生产规模的五步合成轻松获得，并表现出出色的水溶性，再加上其在Caco-2细胞中的高渗透性，使其被归类为BCS I类化合物。它还在所有物种中表现出高代谢稳定性，与啮齿动物中足够的药代动力学特征相关，以及在小鼠辣椒素和部分坐骨神经结扎模型中的抗伤害特性。

更新日期：2020-12-10

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