RT Journal Article
SR Electronic
T1 Biaryl Amides and Hydrazones as Therapeutics for Prion Disease in Transgenic Mice
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 325
OP 338
DO 10.1124/jpet.113.205799
VO 347
IS 2
A1 Duo Lu
A1 Kurt Giles
A1 Zhe Li
A1 Satish Rao
A1 Elena Dolghih
A1 Joel R. Gever
A1 Michal Geva
A1 Manuel L. Elepano
A1 Abby Oehler
A1 Clifford Bryant
A1 Adam R. Renslo
A1 Matthew P. Jacobson
A1 Stephen J. DeArmond
A1 B. Michael Silber
A1 Stanley B. Prusiner
YR 2013
UL http://jpet.aspetjournals.org/content/347/2/325.abstract
AB 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.