title: Biaryl amides and hydrazones as therapeutics for prion disease in transgenic mice.
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.
authors: Institute for Neurodegenerative Diseases (D.L., K.G., Z.L., S.R., J.R.G., M.G., M.L.E., S.J.D., B.M.S., S.B.P.), Department of Neurology (K.G., Z.L., S.R., J.R.G., B.M.S., S.B.P.), Department of Pathology (A.O., S.J.D.), Department of Pharmaceutical Chemistry (E.D., C.B., A.R.R., M.P.J.), Department of Bioengineering and Therapeutic Sciences (B.M.S.), and Small Molecule Discovery Center (C.B., A.R.R.), University of California, San Francisco, California.
authors: Duo
authors: D
authors: Lu
authors: Kurt
authors: K
authors: Giles
authors: Zhe
authors: Z
authors: Li
authors: Satish
authors: S
authors: Rao
authors: Elena
authors: E
authors: Dolghih
authors: Joel R
authors: JR
authors: Gever
authors: Michal
authors: M
authors: Geva
authors: Manuel L
authors: ML
authors: Elepano
authors: Abby
authors: A
authors: Oehler
authors: Clifford
authors: C
authors: Bryant
authors: Adam R
authors: AR
authors: Renslo
authors: Matthew P
authors: MP
authors: Jacobson
authors: Stephen J
authors: SJ
authors: Dearmond
authors: B Michael
authors: BM
authors: Silber
authors: Stanley B
authors: SB
authors: Prusiner
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D055256:Infectious Disease Incubation Period; D053208:Kaplan-Meier Estimate; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D015394:Molecular Structure; D018620:PrPSc Proteins / Q000235:genetics / Q000472:pathogenicity*; D017096:Prion Diseases / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D006835:Hydrazones; D018620:PrPSc Proteins
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