Discovery of PIPE-359, a Brain-Penetrant, Selective M Receptor Antagonist with Robust Efficacy in Murine MOG-EAE.
Basic Information
ID: ALA4673395
Journal: ACS Med Chem Lett
Title: Discovery of PIPE-359, a Brain-Penetrant, Selective M Receptor Antagonist with Robust Efficacy in Murine MOG-EAE.
Authors: Schrader TO,Xiong Y,Lorenzana AO,Broadhead A,Stebbins KJ,Poon MM,Baccei C,Lorrain DS
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.
CiteXplore: 33488977
DOI: 10.1021/acsmedchemlett.0c00626
Patent ID: ┄