PIPE-359的发现，一种具有脑渗透性的选择性M受体拮抗剂，在小鼠MOG-EAE模型中具有强大疗效。
Discovery of PIPE-359, a Brain-Penetrant, Selective M Receptor Antagonist with Robust Efficacy in Murine MOG-EAE.
作者信息
Schrader Thomas O, Xiong Yifeng, Lorenzana Ariana O, Broadhead Alexander, Stebbins Karin J, Poon Michael M, Baccei Christopher, Lorrain Daniel S
机构信息
Pipeline Therapeutics, 10578 Science Center Drive, Suite 200, San Diego, California 92121, United States.
出版信息
ACS Med Chem Lett. 2020 Dec 24;12(1):155-161. doi: 10.1021/acsmedchemlett.0c00626. eCollection 2021 Jan 14.
Abstract
The discovery of PIPE-359, a brain-penetrant and selective antagonist of the muscarinic acetylcholine receptor subtype 1 is described. Starting from a literature-reported M antagonist, linker replacement and structure-activity relationship investigations of the eastern 1-(pyridinyl)piperazine led to the identification of a novel, potent, and selective antagonist with good MDCKII-MDR1 permeability. Continued semi-iterative positional scanning facilitated improvements in the metabolic and hERG profiles, which ultimately delivered PIPE-359. This advanced drug candidate exhibited robust efficacy in mouse myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis (EAE), a preclinical model for multiple sclerosis.
摘要
本文描述了1型毒蕈碱型乙酰胆碱受体的脑渗透性选择性拮抗剂PIPE-359的发现过程。从文献报道的M拮抗剂出发，通过连接基团替换以及对1-(吡啶基)哌嗪东侧进行构效关系研究，鉴定出一种新型、强效且具有选择性的拮抗剂，其在MDCKII-MDR1模型中具有良好的通透性。持续进行的半迭代位置扫描促进了代谢和hERG特性的改善，最终得到了PIPE-359。这种先进的候选药物在小鼠髓鞘少突胶质细胞糖蛋白(MOG)诱导的实验性自身免疫性脑脊髓炎(EAE，一种多发性硬化症的临床前模型)中显示出强大的疗效。
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