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. We evaluated high-throughput screening hits with the aryl amide scaffold and explored the 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 reported to date, the novel aryl amides reported here were ineffective in prolonging the 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 an inevitable consequence of efficacious anti-prion therapeutics.
- Received June 1, 2016.
- Accepted June 16, 2016.
↵1 Current affiliation: Global Blood Therapeutics, South San Francisco, California.
↵2 Current affiliation: Reiley Pharmaceuticals, Inc., San Francisco, California.
This work was supported by the National Institutes of Health National Institute on Aging [Grants AI064709, AG002132, AG010770, AG021601, and AG031220] and by gifts from the Sherman Fairchild Foundation, the Rainwater Charitable Foundation, and the G. Harold and Leila Y. Mathers Charitable Foundation.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics