TY - JOUR T1 - Optimization of aryl amides that extend survival in prion-infected mice JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.116.235556 SP - jpet.116.235556 AU - Kurt Giles AU - David B. Berry AU - Carlo Condello AU - Brittany N. Dugger AU - Zhe Li AU - Abby Oehler AU - Sumita Bhardwaj AU - Manuel Elepano AU - Shenheng Guan AU - B. Michael Silber AU - Steven H. Olson AU - Stanley B. Prusiner Y1 - 2016/01/01 UR - http://jpet.aspetjournals.org/content/early/2016/06/16/jpet.116.235556.abstract N2 - Developing therapeutics for neurodegenerative diseases (NDs) prevalent in the aging population remains a daunting challenge. With the growing understanding that many NDs progress by conformational self-templating of specific proteins, the prototypical prion diseases offer a platform for ND drug discovery. Here we evaluate high-throughput screening hits with the aryl amide scaffold and explore structure - activity relationships around three series differing in their N-aryl core: benzoxazole, benzothiazole, and cyano. Potent anti-prion compounds were advanced to pharmacokinetic studies, and the resulting brain-penetrant leads from each series, together with a related N-aryl piperazine lead, were escalated to long-term dosing and efficacy studies. Compounds from each of the four series doubled the survival of mice infected with a mouse-passaged prion strain. Treatment with aryl amides altered prion strain properties, as evidenced by the distinct patterns of neuropathological deposition of prion protein and associated astrocytic gliosis in the brain. However, none of the aryl amide compounds resulted in drug-resistant prion strains, in contrast to previous studies on compounds with the 2-aminothiazole (2-AMT) scaffold. As seen with 2-AMTs and other effective anti-prion compounds published to date, the novel aryl amides reported here were ineffective in prolonging survival of transgenic mice infected with human prions. Most encouraging is our discovery that aryl amides show that the development of drug resistance is not a certain consequence of efficacious anti-prion therapeutics. ER -