24 research outputs found
Discovery of N‑Substituted Oseltamivir Derivatives as Potent and Selective Inhibitors of H5N1 Influenza Neuraminidase
To
discover group-1-specific neuraminidase (NA) inhibitors that
are especially involved in combating the H5N1 virus, two series of
oseltamivir derivatives were designed and synthesized by targeting
the 150-cavity. Among these, compound <b>20l</b> was the most
potent N1-selective inhibitor, with IC<sub>50</sub> values of 0.0019,
0.0038, and 0.0067 μM against NAs from three H5N1 viruses. These
values are better than those of oseltamivir carboxylate. Compound <b>32</b> was another potent N1-selective inhibitor that exhibited
a 12-fold increase in activity against the H274Y mutant relative to
oseltamivir carboxylate. Molecular docking studies revealed that the
150-cavity was an auxiliary binding site that may contribute to the
high selectivity of these compounds. The present work is a significant
breakthrough in the discovery of potent group-1-specific neuraminidase
inhibitors, which may be further investigated for the treatment of
infection by the H5N1 virus
Structure-Based Design of Novel G‑Protein-Coupled Receptor TAAR1 Agonists as Potential Antipsychotic Drug Candidates
The
existing available antipsychotics have failed to manage the
cognitive impairment of schizophrenia and induced a number of seriously
undesirable effects. Trace amine-associated receptor 1 (TAAR1) has
emerged as an ideal target for the design of antischizophrenia drugs,
with the ability to mediate multiple psychological functions by sensing
endogenous amine-containing metabolites without the side effects of
catalepsy. In this work, a series of novel TAAR1 agonists were designed
based on the structural analysis of the TAAR1 activation pocket. Among
them, 6e displayed a potent TAAR1-Gs/Gq dual-pathway activation property, being different from that
of the clinical drug candidate SEP-363856 with only TAAR1-Gs pathway activation. In rodent models, 6e significantly
alleviated MK-801-induced schizophrenia-like cognitive phenotypes
without inducing catalepsy. Furthermore, 6e·HCl exhibited
favorable pharmacokinetic (T1/2 = 2.31
h, F = 39%) and safety properties. All these demonstrated
that 6e·HCl may be used as a novel drug candidate
for schizophrenia treatment
Structure-Based Design of Novel G‑Protein-Coupled Receptor TAAR1 Agonists as Potential Antipsychotic Drug Candidates
The
existing available antipsychotics have failed to manage the
cognitive impairment of schizophrenia and induced a number of seriously
undesirable effects. Trace amine-associated receptor 1 (TAAR1) has
emerged as an ideal target for the design of antischizophrenia drugs,
with the ability to mediate multiple psychological functions by sensing
endogenous amine-containing metabolites without the side effects of
catalepsy. In this work, a series of novel TAAR1 agonists were designed
based on the structural analysis of the TAAR1 activation pocket. Among
them, 6e displayed a potent TAAR1-Gs/Gq dual-pathway activation property, being different from that
of the clinical drug candidate SEP-363856 with only TAAR1-Gs pathway activation. In rodent models, 6e significantly
alleviated MK-801-induced schizophrenia-like cognitive phenotypes
without inducing catalepsy. Furthermore, 6e·HCl exhibited
favorable pharmacokinetic (T1/2 = 2.31
h, F = 39%) and safety properties. All these demonstrated
that 6e·HCl may be used as a novel drug candidate
for schizophrenia treatment
Structure-Based Design of Novel G‑Protein-Coupled Receptor TAAR1 Agonists as Potential Antipsychotic Drug Candidates
The
existing available antipsychotics have failed to manage the
cognitive impairment of schizophrenia and induced a number of seriously
undesirable effects. Trace amine-associated receptor 1 (TAAR1) has
emerged as an ideal target for the design of antischizophrenia drugs,
with the ability to mediate multiple psychological functions by sensing
endogenous amine-containing metabolites without the side effects of
catalepsy. In this work, a series of novel TAAR1 agonists were designed
based on the structural analysis of the TAAR1 activation pocket. Among
them, 6e displayed a potent TAAR1-Gs/Gq dual-pathway activation property, being different from that
of the clinical drug candidate SEP-363856 with only TAAR1-Gs pathway activation. In rodent models, 6e significantly
alleviated MK-801-induced schizophrenia-like cognitive phenotypes
without inducing catalepsy. Furthermore, 6e·HCl exhibited
favorable pharmacokinetic (T1/2 = 2.31
h, F = 39%) and safety properties. All these demonstrated
that 6e·HCl may be used as a novel drug candidate
for schizophrenia treatment
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
Structure-Based Design of Novel G‑Protein-Coupled Receptor TAAR1 Agonists as Potential Antipsychotic Drug Candidates
The
existing available antipsychotics have failed to manage the
cognitive impairment of schizophrenia and induced a number of seriously
undesirable effects. Trace amine-associated receptor 1 (TAAR1) has
emerged as an ideal target for the design of antischizophrenia drugs,
with the ability to mediate multiple psychological functions by sensing
endogenous amine-containing metabolites without the side effects of
catalepsy. In this work, a series of novel TAAR1 agonists were designed
based on the structural analysis of the TAAR1 activation pocket. Among
them, 6e displayed a potent TAAR1-Gs/Gq dual-pathway activation property, being different from that
of the clinical drug candidate SEP-363856 with only TAAR1-Gs pathway activation. In rodent models, 6e significantly
alleviated MK-801-induced schizophrenia-like cognitive phenotypes
without inducing catalepsy. Furthermore, 6e·HCl exhibited
favorable pharmacokinetic (T1/2 = 2.31
h, F = 39%) and safety properties. All these demonstrated
that 6e·HCl may be used as a novel drug candidate
for schizophrenia treatment
Structure-Based Design of Novel G‑Protein-Coupled Receptor TAAR1 Agonists as Potential Antipsychotic Drug Candidates
The
existing available antipsychotics have failed to manage the
cognitive impairment of schizophrenia and induced a number of seriously
undesirable effects. Trace amine-associated receptor 1 (TAAR1) has
emerged as an ideal target for the design of antischizophrenia drugs,
with the ability to mediate multiple psychological functions by sensing
endogenous amine-containing metabolites without the side effects of
catalepsy. In this work, a series of novel TAAR1 agonists were designed
based on the structural analysis of the TAAR1 activation pocket. Among
them, 6e displayed a potent TAAR1-Gs/Gq dual-pathway activation property, being different from that
of the clinical drug candidate SEP-363856 with only TAAR1-Gs pathway activation. In rodent models, 6e significantly
alleviated MK-801-induced schizophrenia-like cognitive phenotypes
without inducing catalepsy. Furthermore, 6e·HCl exhibited
favorable pharmacokinetic (T1/2 = 2.31
h, F = 39%) and safety properties. All these demonstrated
that 6e·HCl may be used as a novel drug candidate
for schizophrenia treatment
Structure-Based Design of Novel G‑Protein-Coupled Receptor TAAR1 Agonists as Potential Antipsychotic Drug Candidates
The
existing available antipsychotics have failed to manage the
cognitive impairment of schizophrenia and induced a number of seriously
undesirable effects. Trace amine-associated receptor 1 (TAAR1) has
emerged as an ideal target for the design of antischizophrenia drugs,
with the ability to mediate multiple psychological functions by sensing
endogenous amine-containing metabolites without the side effects of
catalepsy. In this work, a series of novel TAAR1 agonists were designed
based on the structural analysis of the TAAR1 activation pocket. Among
them, 6e displayed a potent TAAR1-Gs/Gq dual-pathway activation property, being different from that
of the clinical drug candidate SEP-363856 with only TAAR1-Gs pathway activation. In rodent models, 6e significantly
alleviated MK-801-induced schizophrenia-like cognitive phenotypes
without inducing catalepsy. Furthermore, 6e·HCl exhibited
favorable pharmacokinetic (T1/2 = 2.31
h, F = 39%) and safety properties. All these demonstrated
that 6e·HCl may be used as a novel drug candidate
for schizophrenia treatment
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
Lead Optimization and Avoidance of Metabolic-perturbing Motif Developing Novel Diarylpyrimidines as Potent HIV‑1 NNRTIs
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
represent
an indispensable part of anti-HIV-1 therapy. To discover novel HIV-1
NNRTIs with increased drug resistance profiles and improved pharmacokinetic
(PK) properties, a series of novel diarylpyrimidine derivatives were
generated via the cocrystal structure-based drug design strategy.
Among them, 36a exhibited outstanding antiviral activity
against HIV-1 IIIB and a panel of mutant strains (L100I, K103N, Y181C,
Y188L, E138K, F227L + V106A, and RES056), with EC50 ranging
from 2.22 to 53.3 nM. Besides, 36a was identified with
higher binding affinity (KD = 2.50 μM)
and inhibitory activity (IC50 = 0.03 μM) to HIV-1
RT. Molecular docking and molecular dynamics simulation were performed
to rationalize the design and the improved drug resistance of these
novel inhibitors. Additionally, 36a·HCl exhibited
favorable PK (T1/2 = 5.12 h, F = 12.1%) and safety properties (LD50 > 2000 mg/kg).
All
these suggested that 36a·HCl may serve as a novel
drug candidate anti-HIV-1 therapy