Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals S.A., Carrer Baldiri Reixac, 4-8. Parc Científic de Barcelona, 08028 Barcelona, Spain.
WELAB, Parc Científic Barcelona, C/Baldiri Reixac 4-8, 08028 Barcelona, Spain.
J Med Chem. 2021 Apr 22;64(8):5157-5170. doi: 10.1021/acs.jmedchem.1c00244. Epub 2021 Apr 7.
The synthesis and pharmacological activity of a new series of 5a,7,8,8a-tetrahydro-4,6-pyrrolo[3,4-][1,2,3]triazolo[1,5-][1,4]oxazine derivatives as potent sigma-1 receptor (σR) ligands are reported. A lead optimization program aimed at improving the aqueous solubility of parent racemic nonpolar derivatives led to the identification of several σR antagonists with a good absorption, distribution, metabolism, and excretion in vitro profile, no off-target affinities, and characterized by a low basic p (around 5) that correlates with high exposure levels in rodents. Two compounds displaying a differential brain-to-plasma ratio distribution profile, and , exhibited a good analgesic profile and were selected as preclinical candidates for the treatment of pain.
报道了一系列新型 5a,7,8,8a-四氢-4,6-吡咯并[3,4-][1,2,3]三唑并[1,5-][1,4]恶嗪衍生物作为强效σ1 受体（σR）配体的合成和药理学活性。一个旨在提高母体外消旋非极性衍生物的水溶性的先导优化计划导致了几个 σR 拮抗剂的鉴定，这些拮抗剂具有良好的吸收、分布、代谢和体外排泄特征，没有脱靶亲和力，并具有低碱性 p（约 5），这与啮齿动物中的高暴露水平相关。两种显示出不同的脑-血浆比分布特征的化合物 和 ，表现出良好的镇痛作用，被选为治疗疼痛的临床前候选药物。
