Discovery and Preliminary Structure–ActivityRelationship of Arylpiperazines as Novel Brain-Penetrant AntiprionCompounds

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 PrP^Sc) of a normally benign, host cellular protein, denoted PrP^C. We employed high-throughput screening enzyme-linked immunosorbent assays to evaluate compounds for their ability to reduce the level of PrP^Sc in Rocky Mountain Laboratory prion-infected mouse neuroblastoma cells (ScN2a-cl3). Arylpiperazines were among the active compounds identified, 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 furtherlead optimization in our pursuit of potential drug candidates forthe treatment of prion diseases.