6 research outputs found
Target-Induced Horseradish Peroxidase Deactivation for Multicolor Colorimetric Assay of Hydrogen Sulfide in Rat Brain Microdialysis
Hydrogen sulfide
(H<sub>2</sub>S) is important for normal neural
functions, which involves protecting neurons from oxidative stress
and neuronal transmission modulation in brain. The detection of H<sub>2</sub>S is significant for revealing its role in the diagnosis of
various disease. In this study, a novel multicolor colorimetric assay
based on the etching of gold nanorods (Au NRs) is proposed to evaluate
H<sub>2</sub>S level with the naked eye. This measurement relies on
the catalytic oxidation of 3,3′,5,5′-tetramethylbenzidine
(TMB) via horseradish peroxidase (HRP) to produce TMB<sup>2+</sup>, which could etch the Au NRs quickly and accompany with a distinct
color change. The vivid colors can be easily distinguished with the
naked eye without any sophisticated instruments. The presence of H<sub>2</sub>S can cause the deactivation of HRP, which affects the amount
of TMB<sup>2+</sup> produced and consequently affects the color changing
of the system. Based on this mechanism, a simple but sensitive multicolor
colorimetric assay is developed for H<sub>2</sub>S detection with
a linear range of 0.05–50 μM. The proposed method is
demonstrated for monitoring extracellular H<sub>2</sub>S in rat brain
coupled with microdialysate
Map of district-level trachoma prevalence surveys included in the cost analysis.
<p>Map of district-level trachoma prevalence surveys included in the cost analysis.</p
Average proportion of total survey costs attributed to cost categories and activities.
<p>Average proportion of total survey costs attributed to cost categories and activities.</p
Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection
The discovery of BMS-605339 (<b>35</b>), a tripeptidic inhibitor of the NS3/4A enzyme, is described.
This compound incorporates a cyclopropylÂacylsulfonamide moiety
that was designed to improve the potency of carboxylic acid prototypes
through the introduction of favorable nonbonding interactions within
the S1′ site of the protease. The identification of <b>35</b> was enabled through the optimization and balance of critical properties
including potency and pharmacokinetics (PK). This was achieved through
modulation of the P2* subsite of the inhibitor which identified the
isoquinoline ring system as a key template for improving PK properties
with further optimization achieved through functionalization. A methoxy
moiety at the C6 position of this isoquinoline ring system proved
to be optimal with respect to potency and PK, thus providing the clinical
compound <b>35</b> which demonstrated antiviral activity in
HCV-infected patients
Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing
The
discovery of a back-up to the hepatitis C virus NS3 protease inhibitor
asunaprevir (<b>2</b>) is described. The objective of this work
was the identification of a drug with antiviral properties and toxicology
parameters similar to <b>2</b>, but with a preclinical pharmacokinetic
(PK) profile that was predictive of once-daily dosing. Critical to
this discovery process was the employment of an ex vivo cardiovascular
(CV) model which served to identify compounds that, like <b>2</b>, were free of the CV liabilities that resulted in the discontinuation
of BMS-605339 (<b>1</b>) from clinical trials. Structure–activity
relationships (SARs) at each of the structural subsites in <b>2</b> were explored with substantial improvement in PK through modifications
at the P1 site, while potency gains were found with small, but rationally
designed structural changes to P4. Additional modifications at P3
were required to optimize the CV profile, and these combined SARs
led to the discovery of BMS-890068 (<b>29</b>)