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Identification of Potent Ebola Virus Entry Inhibitors with Suitable Properties for in Vivo Studies
- Source :
- Journal of medicinal chemistry. 61(14)
- Publication Year :
- 2018
-
Abstract
- Previous studies identified an adamantane dipeptide piperazine 3.47 that inhibits Ebola virus (EBOV) infection by targeting the essential receptor Niemann–Pick C1 (NPC1). The physicochemical properties of 3.47 limit its potential for testing in vivo. Optimization by improving potency, reducing hydrophobicity, and replacing labile moieties identified 3.47 derivatives with improved in vitro ADME properties that are also highly active against EBOV infection, including when tested in the presence of 50% normal human serum (NHS). In addition, 3A4 was identified as the major cytochrome P450 isoform that metabolizes these compounds, and accordingly, mouse microsome stability was significantly improved when tested in the presence of the CYP3A4 inhibitor ritonavir that is approved for clinical use as a booster of anti-HIV drugs. Oral administration of the EBOV inhibitors with ritonavir resulted in a pharmacokinetic profile that supports a b.i.d. dosing regimen for efficacy studies in mice.
- Subjects :
- 0301 basic medicine
030106 microbiology
Drug Evaluation, Preclinical
Pharmacology
medicine.disease_cause
03 medical and health sciences
Pharmacokinetics
In vivo
Drug Discovery
Chlorocebus aethiops
medicine
Potency
Animals
Humans
Vero Cells
ADME
Ebola virus
Chemistry
Esters
Virus Internalization
Ebolavirus
In vitro
030104 developmental biology
Microsome
Molecular Medicine
Ritonavir
Hydrophobic and Hydrophilic Interactions
medicine.drug
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 61
- Issue :
- 14
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....71cbfe54eee01b16adc00977e7d3d83f