Welab Barcelona, Parc Científic Barcelona, C/Baldiri Reixac 4-8, Barcelona 08028, Spain.
J Med Chem. 2024 Jun 13;67(11):9150-9164. doi: 10.1021/acs.jmedchem.4c00288. Epub 2024 May 16.
The synthesis and pharmacological activity of a new series of thieno[2,3-]pyrimidin-4(3)-one derivatives as sigma-1 receptor (σR) ligands are reported. A hit from a high-throughput screening program was evolved into a highly potent and selective σR agonist () that contains a free NH group as positive ionizable moiety, not fulfilling the usual pharmacophoric features of the σR. The compound shows good physicochemical and ADMET characteristics, displays an agonist profile in the binding immunoglobulin protein/σR association assay, induces neuron viability in an in vitro model of β-amyloid peptide intoxication, and presents positive results against recognition memory impairment induced by hippocampal injection of Aβ peptide in rats after oral treatment, altogether making (WLB-87848) an interesting candidate for neuroprotection.
报告了一系列新型噻吩并[2,3-d]嘧啶-4(3H)-酮衍生物的合成及药理活性，作为 sigma-1 受体（σR）配体。高内涵筛选计划的一个命中化合物经过进化，成为一种高活性和选择性的 σR 激动剂（），其中包含作为正可离子化部分的游离 NH 基团，不符合 σR 的常见药效特征。该化合物具有良好的理化和 ADMET 特性，在结合免疫球蛋白蛋白/σR 相关测定中显示出激动剂特征，在体外β-淀粉样肽中毒模型中诱导神经元活力，并在大鼠海马注射 Aβ肽后口服治疗引起的识别记忆障碍方面呈现阳性结果，总之，（WLB-87848）是一种有前途的神经保护候选药物。
