Abstract
The only small-molecule compound demonstrated to substantially extend survival in prion-infected mice is a biaryl hydrazone termed "Compd B." 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 and 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. In addition, we applied bioluminescence imaging, previously shown to detect prion disease onset in live mice earlier than clinical signs, and demonstrated it was possible to predict drug efficacy in two lines of prion-infected transgenic mice expressing a luciferase reporter long before extension in survival could be measured.
- The American Society for Pharmacology and Experimental Therapeutics