Discovery and Preliminary Structure-Activity Relationship of Arylpiperazines as Novel, Brain-Penetrant Antiprion Compounds

摘要

Creutzfeldt-Jakob disease and kuru in humans, BSE in cattle, and scrapie in sheep are fatal neurodegenerative disorders. Such illnesses are caused by the conversion and accumulation of a misfolded pathogenic isoform (termed PrPSc ) of a normally benign, host cellular protein, denoted PrPC. We employed high-throughput screening enzyme-linked immunosorbent assays to evaluate compounds for their ability to reduce the level of PrPSc in Rocky Mountain Laboratory prion-infected mouse neuroblastoma cells (ScN2a-cl3). Arylpiperazines were among the active compounds identi?ed, but the initial hits suffered from low potency and poor drug-likeness. The best of those hits, such as 1, 7, 13, and 19, displayed moderate antiprion activity with EC50 values in the micromolar range. Key analogues were designed and synthesized on the basis of the structure-activity relationship, with analogues 41, 44, 46, and 47 found to have submicromolar potency. Analogues 41 and 44 were able to penetrate the blood-brain barrier and achieved excellent drug concentrations in the brains of mice after oral dosing. These compounds represent good starting points for further lead optimization in our pursuit of potential drug candidates for the treatment of prion diseases.