Discovery of PIPE-359, a Brain-Penetrant, Selective M1 Receptor Antagonist with Robust Efficacy in Murine MOG-EAE

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-1 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.

Automated summary

The discovery and development of PIPE-359, a brain-penetrant selective antagonist of the muscarinic acetylcholine receptor subtype 1, is described. This compound showed good permeability and selectivity, as well as robust efficacy in a preclinical model for multiple sclerosis. Initial modifications and iterative scanning led to improvements in metabolic and hERG profiles, ultimately resulting in the successful development of PIPE-359.