TY - JOUR
T1 - Identification of Potent Ebola Virus Entry Inhibitors with Suitable Properties for in Vivo Studies
AU - Liu, Hu
AU - Tian, Ye
AU - Lee, Kyungae
AU - Krishnan, Pranav
AU - Wang, May Kwang Mei
AU - Whelan, Sean
AU - Mevers, Emily
AU - Soloveva, Veronica
AU - Dedic, Benjamin
AU - Liu, Xinyong
AU - Cunningham, James M.
N1 - Funding Information:
This work was supported by NIH/NIAID grant 1U19AI109740 awarded to J.M.C and S.W. M.K.W. was supported by NIH grant F31AI131452.
Publisher Copyright:
Copyright © 2018 American Chemical Society.
PY - 2018/7/26
Y1 - 2018/7/26
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85048900226
U2 - 10.1021/acs.jmedchem.8b00704
DO - 10.1021/acs.jmedchem.8b00704
M3 - Article
C2 - 29920098
AN - SCOPUS:85048900226
SN - 0022-2623
VL - 61
SP - 6293
EP - 6307
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 14
ER -