title: Discovery and Preliminary SAR of Arylpiperazines as Novel, Brainpenetrant Antiprion Compounds.
abstract: Prion diseases are a group of fatal neurodegenerative disorders that include Creutzfeldt-Jakob disease (CJD) and kuru in humans, BSE in cattle, and scrapie in sheep. 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 (HTS) ELISAs to evaluate compounds for their ability to reduce the level of PrPScin Rocky Mountain Laboratory (RML) 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 as1,7,13, and19, displayed moderate antiprion activity with EC50values in the micromolar range. Key analogs were designed and synthesized based on the SAR, with analogs41,44,46, and47found to have sub-micromolar potency. Analogs41and44were able to penetrate the blood-brain barrier (BBB) 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.
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, California ; Department of Neurology, University of California, San Francisco, California.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.forename: Joel
authors.initials: J
authors.lastname: Gever
authors.forename: Satish
authors.initials: S
authors.lastname: Rao
authors.forename: Kartika
authors.initials: K
authors.lastname: Widjaja
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
authors.forename: B Michael
authors.initials: BM
authors.lastname: Silber
keywords: Creutzfeldt-Jakob disease; Neurodegenerative diseases; SAR; arylpiperazine; piperazine; prion disease