2 research outputs found
Identification of Potent Ebola Virus Entry Inhibitors with Suitable Properties for in Vivo Studies
Previous
studies identified an adamantane dipeptide piperazine <b>3.47</b> that inhibits Ebola virus (EBOV) infection by targeting
the essential receptor Niemann–Pick C1 (NPC1). The physicochemical
properties of <b>3.47</b> limit its potential for testing in
vivo. Optimization by improving potency, reducing hydrophobicity,
and replacing labile moieties identified <b>3.47</b> 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
Identification of Potent Ebola Virus Entry Inhibitors with Suitable Properties for in Vivo Studies
Previous
studies identified an adamantane dipeptide piperazine <b>3.47</b> that inhibits Ebola virus (EBOV) infection by targeting
the essential receptor Niemann–Pick C1 (NPC1). The physicochemical
properties of <b>3.47</b> limit its potential for testing in
vivo. Optimization by improving potency, reducing hydrophobicity,
and replacing labile moieties identified <b>3.47</b> 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