Optimization of aryl amides that extend survival in prion-infected mice

Kurt Giles, David B. Berry, Carlo Condello, Brittany Dugger, Zhe Li, Abby Oehler, Sumita Bhardwaj, Manuel Elepano, Shenheng Guan, B. Michael Silber, Steven H. Olson, Stanley B. Prusiner

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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 brainpenetrant 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.

Original languageEnglish (US)
Pages (from-to)537-547
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume358
Issue number3
DOIs
StatePublished - Sep 1 2016

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Prions
Amides
Survival
Neurodegenerative Diseases
Benzoxazoles
Prion Diseases
Gliosis
Drug Discovery
Structure-Activity Relationship
Drug Resistance
Transgenic Mice
Pharmacokinetics
Brain
Therapeutics
Pharmaceutical Preparations
Population

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Optimization of aryl amides that extend survival in prion-infected mice. / Giles, Kurt; Berry, David B.; Condello, Carlo; Dugger, Brittany; Li, Zhe; Oehler, Abby; Bhardwaj, Sumita; Elepano, Manuel; Guan, Shenheng; Silber, B. Michael; Olson, Steven H.; Prusiner, Stanley B.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 358, No. 3, 01.09.2016, p. 537-547.

Research output: Contribution to journalArticle

Giles, K, Berry, DB, Condello, C, Dugger, B, Li, Z, Oehler, A, Bhardwaj, S, Elepano, M, Guan, S, Silber, BM, Olson, SH & Prusiner, SB 2016, 'Optimization of aryl amides that extend survival in prion-infected mice', Journal of Pharmacology and Experimental Therapeutics, vol. 358, no. 3, pp. 537-547. https://doi.org/10.1124/jpet.116.235556
Giles, Kurt ; Berry, David B. ; Condello, Carlo ; Dugger, Brittany ; Li, Zhe ; Oehler, Abby ; Bhardwaj, Sumita ; Elepano, Manuel ; Guan, Shenheng ; Silber, B. Michael ; Olson, Steven H. ; Prusiner, Stanley B. / Optimization of aryl amides that extend survival in prion-infected mice. In: Journal of Pharmacology and Experimental Therapeutics. 2016 ; Vol. 358, No. 3. pp. 537-547.
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