39 research outputs found
A Novel Small Molecule Inhibitor of Hepatitis C Virus Entry
Small molecule inhibitors of hepatitis C virus (HCV) are being developed to complement or replace treatments with pegylated interferons and ribavirin, which have poor response rates and significant side effects. Resistance to these inhibitors emerges rapidly in the clinic, suggesting that successful therapy will involve combination therapy with multiple inhibitors of different targets. The entry process of HCV into hepatocytes represents another series of potential targets for therapeutic intervention, involving viral structural proteins that have not been extensively explored due to experimental limitations. To discover HCV entry inhibitors, we utilized HCV pseudoparticles (HCVpp) incorporating E1-E2 envelope proteins from a genotype 1b clinical isolate. Screening of a small molecule library identified a potent HCV-specific triazine inhibitor, EI-1. A series of HCVpp with E1-E2 sequences from various HCV isolates was used to show activity against all genotype 1a and 1b HCVpp tested, with median EC50 values of 0.134 and 0.027 µM, respectively. Time-of-addition experiments demonstrated a block in HCVpp entry, downstream of initial attachment to the cell surface, and prior to or concomitant with bafilomycin inhibition of endosomal acidification. EI-1 was equally active against cell-culture adapted HCV (HCVcc), blocking both cell-free entry and cell-to-cell transmission of virus. HCVcc with high-level resistance to EI-1 was selected by sequential passage in the presence of inhibitor, and resistance was shown to be conferred by changes to residue 719 in the carboxy-terminal transmembrane anchor region of E2, implicating this envelope protein in EI-1 susceptibility. Combinations of EI-1 with interferon, or inhibitors of NS3 or NS5A, resulted in additive to synergistic activity. These results suggest that inhibitors of HCV entry could be added to replication inhibitors and interferons already in development
Using One- and Two-Dimensional NMR Techniques to Characterize Reaction Products Bound to Chiron SynPhase Crowns
Ligand-Based Discovery of a New Scaffold for Allosteric Modulation of the μ-Opioid 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
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
Ligand-Based Discovery of a New Scaffold for Allosteric Modulation of the μ‑Opioid Receptor
With
the hope of discovering effective analgesics with fewer side
effects, attention has recently shifted to allosteric modulators of
the opioid receptors. In the past two years, the first chemotypes
of positive or silent allosteric modulators (PAMs or SAMs, respectively)
of μ- and δ-opioid receptor types have been reported in
the literature. During a structure-guided lead optimization campaign
with μ-PAMs BMS-986121 and BMS-986122 as starting compounds,
we discovered a new chemotype that was confirmed to display μ-PAM
or μ-SAM activity depending on the specific substitutions as
assessed by endomorphin-1-stimulated β-arrestin2 recruitment
assays in Chinese Hamster Ovary (CHO)-μ PathHunter cells. The
most active μ-PAM of this series was analyzed further in competition
binding and G-protein activation assays to understand its effects
on ligand binding and to investigate the nature of its probe dependence