Tilorone dihydrochloride (tilorone) is a small-molecule, orally bioavailable drug that is used clinically as an antiviral outside of the US. A machine learning model trained on anti-Ebola virus (EBOV) screening data previously identified tilorone as a potent in vitro EBOV inhibitor, making it a candidate for the treatment of Ebola virus disease (EVD). In the present study, a series of in vitro ADMET (absorption, distribution, metabolism, excretion, toxicity) assays demonstrated the drug has excellent solubility, high Caco-2 permeability, was not a P-glycoprotein substrate and had no inhibitory activity against five human CYP450 enzymes (3A4, 2D6, 2C19, 2C9 and 1A2). Tilorone was shown to have 52% human plasma protein binding with excellent plasma stability and a mouse liver microsome half-life of 48 minutes. Dose range-finding studies in mice demonstrated a maximum tolerated single dose of 100 mg/kg. A pharmacokinetics study in mice at 2 and 10 mg/kg dose levels showed that the drug is rapidly absorbed, has dose-dependent increases in Cmax and AUC values with a half-life of approximately 18 hours in both males and females, although the exposure was ~2.5-fold higher in male mice. Tilorone doses of 25 and 50 mg/kg proved efficacious in protecting 90% of mice from a lethal challenge with mouse-adapted EBOV (maEBOV) with once daily intraperitoneal (ip) dosing for 8 days. A subsequent study showed that 30 mg/kg/day of tilorone given ip starting 2 or 24 hours post-challenge and continuing through Day 7 post infection was fully protective, indicating promising activity for the treatment of EVD.
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