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Towards optimization of arylamides as novel, potent, and brain-penetrant antiprion lead compounds

  • Author(s): Li, Z
  • Rao, S
  • Gever, JR
  • Widjaja, K
  • Prusiner, SB
  • Michael Silber, B
  • et al.

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The prion diseases caused by PrPSc, an alternatively folded form of the cellular prion protein (PrPC), are rapidly progressive, fatal, and untreatable neurodegenerative disorders. We employed HTS ELISA assays to identify compounds that lower the level of PrPScin prion-infected mouse neuroblastoma (ScN2a-cl3) cells and identified a series of arylamides. Structure-activity relationship (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 EC50of 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 analogues, including a set with biaryl groups introduced on the carbonyl side for improved potency. Several of these biaryl analogues have submicromolar potency, with the most potent analogue 17 having an EC50= 22 nM. More importantly, 17 and several biarylamides (20, 24, 26, and 27) were able to traverse the blood-brain barrier (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. © 2013 American Chemical Society.

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