The prion diseases caused by PrPSc, an alternatively folded form of the cellular prion protein (PrPC), are rapidly progressive, fatal, and untreatable neurodegenerative syndromes. We employed HTS ELISA assays to identify compounds that lower the level of PrPSc in prion-infected mouse neuroblastoma (ScN2a-cl3) cells and identified a series of arylamides. SAR studies indicated that small amides with one aromatic, or heteroaromatic ring, on each side of the amide bond are of modest potency. Of note, benzamide (7), with an EC50 of 2200 nM, was one of only a few arylamide hits with a piperazine group on its aniline moiety. The basic piperazine nitrogen can be protonated at physiologic pH, improving solubility, and therefore we wanted to exploit this feature in our search for a drug candidate. An SAR campaign resulted in several key analogs, including a set with biaryl groups introduced on the carbonyl side for improved potency. Several of these biaryl analogs have submicromolar potency, with the most potent analog 17 having an EC50 = 22 nM. More importantly, 17 and several biarylamides (20, 24, 26, 27) were able to traverse the BBB and displayed excellent drug levels in the brains of mice following oral dosing. These biarylamides may represent good starting points for further lead optimization for the identification of potential drug candidates for the treatment of prion diseases.