title: Optimization of Arylamides as Novel, Potent and Brain-penetrant Antiprion Lead Compounds.
abstract: 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 PrPScin 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 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 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 analog17having an EC50= 22 nM. More importantly,17and 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.
authors: Institute for Neurodegenerative Diseases, University of California, San Francisco, California ; Department of Neurology, University of California, San Francisco, California ; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California.
authors: Zhe
authors: Z
authors: Li
authors: Satish
authors: S
authors: Rao
authors: Joel R
authors: JR
authors: Gever
authors: Kartika
authors: K
authors: Widjaja
authors: Stanley B
authors: SB
authors: Prusiner
authors: B Michael
authors: BM
authors: Silber
keywords: Creutzfeldt-Jakob disease; Neurodegenerative diseases; SAR; amide; arylamide; prion disease
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