14 research outputs found
Solid Phase Synthesis of 1,5-Diarylpyrazole-4-carboxamides: Discovery of Antagonists of the CB-1 Receptor
We have developed a solid phase synthesis route to 1,5-substituted
pyrazole-4-carboxamides with three diversity points aimed at the discovery
of new compounds as potential G-Protein coupled receptor (GPCR) ligands.
The new chemistry involves acylation of a resin bound secondary amine
with a β-ketoester via transamidation, conversion of the resulting
β-ketoamide to the corresponding vinylogous amide, pyrazole
formation upon reaction with a aryl hydrzine, and cleavage of the
product from the resin. Using the reported methodology, we describe
the syntheses of multiple arrays of pyrazoles that were used collectively
to construct a library of more than 1000 analogues. Several members
of this library displayed submicromolar antagonist activities at the
cannabinoid subtype 1 (CB-1) receptor
Solid Phase Synthesis of 1,5-Diarylpyrazole-4-carboxamides: Discovery of Antagonists of the CB-1 Receptor
We have developed a solid phase synthesis route to 1,5-substituted
pyrazole-4-carboxamides with three diversity points aimed at the discovery
of new compounds as potential G-Protein coupled receptor (GPCR) ligands.
The new chemistry involves acylation of a resin bound secondary amine
with a β-ketoester via transamidation, conversion of the resulting
β-ketoamide to the corresponding vinylogous amide, pyrazole
formation upon reaction with a aryl hydrzine, and cleavage of the
product from the resin. Using the reported methodology, we describe
the syntheses of multiple arrays of pyrazoles that were used collectively
to construct a library of more than 1000 analogues. Several members
of this library displayed submicromolar antagonist activities at the
cannabinoid subtype 1 (CB-1) receptor
Solid Phase Synthesis of 1,5-Diarylpyrazole-4-carboxamides: Discovery of Antagonists of the CB-1 Receptor
We have developed a solid phase synthesis route to 1,5-substituted
pyrazole-4-carboxamides with three diversity points aimed at the discovery
of new compounds as potential G-Protein coupled receptor (GPCR) ligands.
The new chemistry involves acylation of a resin bound secondary amine
with a β-ketoester via transamidation, conversion of the resulting
β-ketoamide to the corresponding vinylogous amide, pyrazole
formation upon reaction with a aryl hydrzine, and cleavage of the
product from the resin. Using the reported methodology, we describe
the syntheses of multiple arrays of pyrazoles that were used collectively
to construct a library of more than 1000 analogues. Several members
of this library displayed submicromolar antagonist activities at the
cannabinoid subtype 1 (CB-1) receptor
Solid Phase Synthesis of 1,5-Diarylpyrazole-4-carboxamides: Discovery of Antagonists of the CB-1 Receptor
We have developed a solid phase synthesis route to 1,5-substituted
pyrazole-4-carboxamides with three diversity points aimed at the discovery
of new compounds as potential G-Protein coupled receptor (GPCR) ligands.
The new chemistry involves acylation of a resin bound secondary amine
with a β-ketoester via transamidation, conversion of the resulting
β-ketoamide to the corresponding vinylogous amide, pyrazole
formation upon reaction with a aryl hydrzine, and cleavage of the
product from the resin. Using the reported methodology, we describe
the syntheses of multiple arrays of pyrazoles that were used collectively
to construct a library of more than 1000 analogues. Several members
of this library displayed submicromolar antagonist activities at the
cannabinoid subtype 1 (CB-1) receptor
Schematic diagram of the HCV E2 protein and sequences of the region encompassing the EI-1 resistance residue.
<p>Previously defined regions of the protein are indicated by the shaded boxes. Numbers correspond to the HCV polyprotein amino acid positions in E2. HVR1, hypervariable region 1. HVR2, hypervariable region 2. pFP<sub>1</sub> and pFP<sub>2</sub>, putative fusion peptide regions. igVR, intergenotypic variability region. HR, heptad repeat. TMD, transmembrane domain. The asterisk indicates the position of residue 719 that is involved in EI-1 resistance. The protein sequence alignment from amino acids 709–729 for each of the HCVpp genotype isolates from <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1001086#ppat-1001086-g002" target="_blank">Figure 2</a> is shown. The shaded residues are part of the TMD.</p
Effect of EI-1 on HCV cell-to-cell spread.
<p>(A) Huh-7.5 cells were infected with 0.001 ffu/cell HCVcc-1a/2a at 37°C. At 12 hrs post infection, the inoculum was removed and replaced with medium +1% agarose overlay containing EI-1 (0.5 µM) or DMSO and the cultures were incubated at 37°C for 2, 3 or 4 days. Infected cells were labeled by indirect immunofluorescence using an anti-HCV core monoclonal antibody (green) and nuclei were stained with Hoechst 3325 (red). Images were captured using a Nikon Eclipse TE300 inverted epi-fluorescence microscope. (B) The mean number and standard deviation of infected cells/focus was determined from visual counting of infected cells in ≥100 foci for each time point. (C) The mean number and standard deviation of foci/well was determined at 2 and 4 days post infection.</p
Structure-activity-relationship of the EI-1 chemotype.
a<p>Mean of ≥3 independent experiments.</p>b<p>R, aniline ring substituent (<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1001086#ppat-1001086-g001" target="_blank">Fig 1A</a>).</p
Activity of EI-1 in infectious virus assays.
a<p>Mean of ≥4 independent experiments.</p
Compound structure and activity in the HCVpp assay.
<p>(A) Structure of EI-1. (B) Dose dependent inhibition of HCVpp-1b infectivity by EI-1. Huh-H1 cells were infected with HCVpp-1b or VSVpp in the presence of various concentrations of EI-1, incubated at 37°C, and luciferase activity was measured 3 days post infection. Data are presented as percent inhibition relative to control infections lacking compound. Results are expressed as mean and standard deviation from triplicate assays. EI-1 EC<sub>50</sub> values are 0.016±0.001 and 33±2.1µM for HCVpp and VSVpp, respectively.</p
HCV genotype coverage of EI-1.
<p>Huh-H1 cells were mixed with HCVpp or VSVpp in the presence of various concentrations of EI-1. Infected cells were incubated at 37°C and luciferase activity was determined 3 days post infection. The average EC<sub>50</sub> (≥2 experiments) of each of the 40 isolates representing HCV genotypes 1–5 (triangles), as well as VSVpp (square), is shown.</p