Discovery of PIPE-359, a Brain-Penetrant, Selective M1 Receptor Antagonist with Robust Efficacy in Murine MOG-EAE
| Autor: | Daniel S. Lorrain, Ariana O Lorenzana, Alexander Broadhead, Christopher Baccei, Xiong Yifeng, Thomas O. Schrader, Michael M Poon, Karin J. Stebbins |
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| Rok vydání: | 2020 |
| Předmět: |
Autoimmune encephalitis
biology 010405 organic chemistry Chemistry Multiple sclerosis Organic Chemistry hERG Antagonist Muscarinic acetylcholine receptor M1 Pharmacology medicine.disease 01 natural sciences Biochemistry 0104 chemical sciences Myelin oligodendrocyte glycoprotein 010404 medicinal & biomolecular chemistry medicine.anatomical_structure Drug Discovery Muscarinic acetylcholine receptor medicine biology.protein Remyelination |
| Zdroj: | ACS Medicinal Chemistry Letters. 12:155-161 |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.0c00626 |
| Popis: | 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 M1 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. |
| Databáze: | OpenAIRE |
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