Biaryl amides and hydrazones as therapeutics for prion disease in transgenic mice

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 347; no. 2; pp. 325 - 338
• Main Authors: Lu, Duo, Giles, Kurt, Li, Zhe, Rao, Satish, Dolghih, Elena, Gever, Joel R, Geva, Michal, Elepano, Manuel L, Oehler, Abby, Bryant, Clifford, Renslo, Adam R, Jacobson, Matthew P, Dearmond, Stephen J, Silber, B Michael, Prusiner, Stanley B
• Format: Journal Article
• Language: English
• Published: United States The American Society for Pharmacology and Experimental Therapeutics 01.11.2013
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacokinetics; Amides - therapeutic use; Animals; Brain - drug effects; Brain - metabolism; Brain - pathology; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Drug Discovery and Translational Medicine; Hydrazones - chemical synthesis; Hydrazones - chemistry; Hydrazones - pharmacokinetics; Hydrazones - therapeutic use; Infectious Disease Incubation Period; Kaplan-Meier Estimate; Mice; Mice, Transgenic; Models, Molecular; Molecular Structure; Prion Diseases - drug therapy; PrPSc Proteins - genetics; PrPSc Proteins - pathogenicity; Structure-Activity Relationship
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.113.205799

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.