Paper Details
- Junji Hosokawa-Muto (Center for Emerging Infectious Diseases, Gifu University / Present address: First Department of Forensic Science, National Research Institute of Police Science / junji@nrips.go.jp)
1) Center for Emerging Infectious Diseases, Gifu University , 2) United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University , 3) Department of Gene and Development, Graduate School of Medicine, Gifu University , 4) Present address: First Department of Forensic Science, National Research Institute of Police Science , 5) Present Address: Department of Chemistry, Faculty of Science Division II, Tokyo University of Science
N,N’-[(Cyclohexylmethylene)di-4,1-phenylene]bis[2-(1-pyrrolidinyl)acetamide] (1) is a novel antiprion compound, termed a designer molecular chaperone, that we recently developed. The administration of compound 1 prolonged the survival time of prion-infected mice and slowed the development of neurological and psychological symptoms in prion-infected macaques. The aim of this study was to investigate the oral toxicity of compound 1 to rats and cynomolgus monkeys. Compound 1 was administered orally to rats at doses of 31.3, 125, and 500 mg/kg. Although two of ten rats died at a dose of 500 mg/kg, no serious safety problems were identified at doses of 31.3 and 125 mg/kg. Repeated oral administration of compound 1 to rats at a dosage of 31.3 mg/kg/day for a week led to no significant toxic effects in the rats. An acute toxicity test in cynomolgus monkeys revealed that the administration of compound 1 at a dose of 60 mg/kg induced vomiting and fecal abnormalities. The monkeys did not die even at a dose of 250 mg/kg. A dose-dependent increase in the plasma concentrations of compound 1 in the cynomolgus monkeys as measured by LC/MS/MS analysis indicated that compound 1 migrated into the bloodstream. These results suggest that compound 1 might have potential as a therapeutic agent for prion diseases.