ArticleThe Journal of pharmacology and experimental therapeutics2013
Biaryl amides and hydrazones as therapeutics for prion disease in transgenic mice.
Article in The Journal of pharmacology and experimental therapeutics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 46 citations in OpenAlex.
- Oligosaccharyltransferase (OST) complex inhibition effectively treats rodent and human prions.PLoS pathogens · 2026Article
- In vivo base editing extends lifespan of a humanized mouse model of prion disease.Nature medicine · 2025Article
- Therapeutic effect of curcumin derivative GT863 on prion-infected mice.Scientific reports · 2025Article
- Combination of Styrylbenzoazole Compound and Hydroxypropyl Methylcellulose Enhances Therapeutic Effect in Prion-Infected Mice.Molecular neurobiology · 2024Article
- Review
- Therapeutic Trial of anle138b in Mouse Models of Genetic Prion Disease.Journal of virology · 2023Article
- Alternating anti-prion regimens reduce combination drug resistance but do not further extend survival in scrapie-infected mice.The Journal of general virology · 2021Article
- Human cerebral organoids as a therapeutic drug screening model for Creutzfeldt-Jakob disease.Scientific reports · 2021Article
- Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints.Nucleic acids research · 2020Article
- Multimodal small-molecule screening for human prion protein binders.The Journal of biological chemistry · 2020Article
- On the Conformational Dynamics of β-Amyloid Forming Peptides: A Computational Perspective.Frontiers in bioengineering and biotechnology · 2020Review
- The role of prion strain diversity in the development of successful therapeutic treatments.Progress in molecular biology and translational science · 2020Review
- Antisense oligonucleotides extend survival of prion-infected mice.JCI insight · 2019Article
- Engineering a murine cell line for the stable propagation of hamster prions.The Journal of biological chemistry · 2019Article
- Rescue of Transgenic Alzheimer's Pathophysiology by Polymeric Cellular Prion Protein Antagonists.Cell reports · 2019Article
- A simple in vitro assay for assessing the efficacy, mechanisms and kinetics of anti-prion fibril compounds.Prion · 2018Article
- Developing Therapeutics for PrP Prion Diseases.Cold Spring Harbor perspectives in medicine · 2017Review
- Insights from Therapeutic Studies for PrP Prion Disease.Cold Spring Harbor perspectives in medicine · 2017Review
- Towards authentic transgenic mouse models of heritable PrP prion diseases.Acta neuropathologica · 2016Article
- Optimization of Aryl Amides that Extend Survival in Prion-Infected Mice.The Journal of pharmacology and experimental therapeutics · 2016Article
Corrections and comments
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Authors and funding
15 authors at 1 institution in 1 country.
Funding
Abstract
The only small-molecule compound demonstrated to substantially extend survival in prion-infected mice is a biaryl hydrazone termed "Compd B" (4-pyridinecarboxaldehyde,2-[4-(5-oxazolyl)phenyl]hydrazone). However, the hydrazone moiety of Compd B results in toxic metabolites, making it a poor candidate for further drug development. We developed a pharmacophore model based on diverse antiprion compounds identified by high-throughput screening; based on this model, we generated biaryl amide analogs of Compd B. Medicinal chemistry optimization led to multiple compounds with increased potency, increased brain concentrations, and greater metabolic stability, indicating that they could be promising candidates for antiprion therapy. Replacing the pyridyl ring of Compd B with a phenyl group containing an electron-donating substituent increased potency, while adding an aryl group to the oxazole moiety increased metabolic stability. To test the efficacy of Compd B, we applied bioluminescence imaging (BLI), which was previously shown to detect prion disease onset in live mice earlier than clinical signs. In our studies, Compd B showed good efficacy in two lines of transgenic mice infected with the mouse-adapted Rocky Mountain Laboratory (RML) strain of prions, but not in transgenic mice infected with human prions. The BLI system successfully predicted the efficacies in all cases long before extension in survival could be observed. Our studies suggest that this BLI system has good potential to be applied in future antiprion drug efficacy studies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.