The SARS-CoV-2 pandemic is currently causing an unprecedented global health emergency
since its emergence in December 2019. In December 2021, the FDA granted emergency use
authorization to nirmatrelvir, a SARS-CoV-2 main protease inhibitor, for treating
infected patients. This peptidomimetic is designed with a nitrile warhead, which forms a
covalent bond to the viral protease. Herein, we investigate nirmatrelvir analogs with
different warheads and their inhibitory activities. In addition, antiviral activities
against human alphacoronavirus 229E was also investigated along with a cell-based assay.
We discovered that the hydroxymethylketone and ketobenzothiazole warheads were
equipotent to the nitrile warhead, suggesting that these analogs can also be used for
treating coronavirus infections.
A series of 5-aryl-2-amino-
i
midazo
t
hia
d
iazole (ITD) derivatives
were identified by a phenotype-based high-throughput screening using
a blood stage
Plasmodium falciparum
(
Pf
) growth inhibition assay. A lead optimization program focused on
improving antiplasmodium potency, selectivity against human kinases,
and absorption, distribution, metabolism, excretion, and toxicity
properties and extended pharmacological profiles culminated in the
identification of
INE963
(
1
), which demonstrates
potent cellular activity against
Pf
3D7 (EC
50
= 0.006 μM) and achieves “artemisinin-like”
kill kinetics
in vitro
with a parasite clearance
time of <24 h. A single dose of 30 mg/kg is fully curative in the
Pf
-humanized severe combined immunodeficient mouse model.
INE963
(
1
) also exhibits a high barrier to resistance
in drug selection studies and a long half-life (
T
1/2
) across species. These properties suggest the significant
potential for
INE963
(
1
) to provide a curative
therapy for uncomplicated malaria with short dosing regimens. For
these reasons,
INE963
(
1
) was progressed
through GLP toxicology studies and is now undergoing Ph1 clinical
trials.
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