氟基序的掺入是一种广泛应用于药物设计以调节活性的策略。物理化学参数,和化学化合物的代谢稳定性。在这项研究中,我们试图通过在一组能够抑制B型单胺氧化酶的1H-吡咯并[3,2-c]喹啉中引入氟原子来降低对醚相关基因(hERG)通道的亲和力(MAO-B)。通过体外评估MAO-B抑制和hERG通道的抗靶向,进行了一系列结构修饰。由此鉴定出1-(3-氯苄基)-4-(4,4-二氟哌啶-1-基)-1H-吡咯并[3,2-c]喹啉(26)。化合物26作为可逆的MAO-B抑制剂,在45个靶标上表现出选择性,酶,运输商,和离子通道,并在培养的星形胶质细胞中显示出有效的神经胶质保护特性。此外,该化合物在大鼠肝微粒体试验中表现出良好的代谢稳定性,良好的安全状况,和大脑渗透性。它还在大鼠的新型物体识别测试中显示出促认知作用,在小鼠的强迫游泳测试中显示出抗抑郁样活性。研究结果表明,可逆性MAO-B抑制剂在阿尔茨海默病中具有潜在的治疗应用。
The incorporation of the fluorine motif is a strategy widely applied in drug design for modulating the activity, physicochemical parameters, and metabolic stability of chemical compounds. In this study, we attempted to reduce the affinity for ether-à-go-go-related gene (hERG) channel by introducing fluorine atoms in a group of 1H-pyrrolo[3,2-c]quinolines that are capable of inhibiting monoamine oxidase type B (MAO-B). A series of structural modifications guided by in vitro evaluation of MAO-B inhibition and antitargeting for hERG channels were performed, which led to the identification of 1-(3-chlorobenzyl)-4-(4,4-difluoropiperidin-1-yl)-1H-pyrrolo[3,2-c]quinoline (26). Compound 26 acted as a reversible MAO-B inhibitor exhibiting selectivity over 45 targets, enzymes, transporters, and ion channels, and showed potent glioprotective properties in cultured astrocytes. In addition, the compound demonstrated good metabolic stability in rat liver microsomes assay, a favorable safety profile, and brain permeability. It also displayed procognitive effects in the novel object recognition test in rats and antidepressant-like activity in forced swim test in mice. The findings of the study suggest that reversible MAO-B inhibitors can have potential therapeutic applications in Alzheimer\'s disease.