Oral toxicity study of an antiprion compound <i>N</i>,<i>N</i><i>’</i>-[(cyclohexylmethylene)di-4,1-phenylene]bis[2-(1-pyrrolidinyl)acetamide] in rats and cynomolgus monkeys

Abstract

-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.

The Compelling Demand for an Effective PrPC-Directed Therapy against Prion Diseases

“…For what concerns 2 , a recent multidisciplinary study described this compound as a molecular chaperone showing high affinity for PrP C and efficacy in cell-based assays . Preliminary data on animal models and toxicity studies underline the therapeutic potential of this agent, that however still requires further optimization and characterization to be considered as a valid clinical candidate. , It is worth noting that, beyond the examples just mentioned, the vast majority of molecules claimed as PrP C binders had low binding specificity, inconsistencies between ligand binding affinity and in vitro active concentrations, and lack of in vivo efficacy. In this context, very recently an emblematic work by Reidenbach et al clearly demonstrated that PrP C is a challenging target for small-molecule ligands.…”