Showing papers by "Pierre L. Beaulieu published in 2010"
TL;DR: This work describes an example where a ligand's "structural hinge" influences potency by inducing an "L-shape" bioactive conformation, and due to its solvent exposure in the complex, reasonable conformation-activity-relationships can be qualitatively attributed.
Abstract: Significant advances have led to receptor induced-fit and conformational selection models for describing bimolecular recognition, but a more comprehensive view must evolve to also include ligand shape and conformational changes. Here, we describe an example where a ligand's "structural hinge" influences potency by inducing an "L-shape" bioactive conformation, and due to its solvent exposure in the complex, reasonable conformation-activity-relationships can be qualitatively attributed. From a ligand design perspective, this feature was exploited by successful linker hopping to an alternate "structural hinge" that led to a new and promising chemical series which matched the ligand bioactive conformation and the pocket bioactive space. Using a combination of X-ray crystallography, NMR and modeling with support from binding-site resistance mutant studies and photoaffinity labeling experiments, we were able to derive inhibitor-polymerase complexes for various chemical series.
40 citations
TL;DR: This operationally simple acid-catalyzed process delivers novel indole derivatives in fair to excellent yields and expands the chemical diversity of substitutions that can be introduced on this medicinally important scaffold.
38 citations
TL;DR: Novel diamide derivatives such as 44 exhibited comparable potency as previously described tryptophan-based inhibitors but physicochemical properties have been improved, resulting in molecules with reduced off-target liabilities (CYP inhibition) and increased metabolic stability.
21 citations
TL;DR: SAR studies at the N(1)-position of allosteric indole-based HCV NS5B inhibitors has led to the discovery of acetamide derivatives with good cellular potency in subgenomic replicons.
19 citations
TL;DR: SAR at the C-2 position of benzimidazole-based Thumb Pocket I inhibitors of HCV NS5B polymerase revealed parallel activity for distinct sub-series that harbor 5-hydroxytryptophan amides, neutral thiazole isosteres or recently disclosed cinnamic acid diamides.
12 citations
Journal Article•
TL;DR: In phase I and a IIa clinical trial in treatment-naïve patients infected with genotype 1 HCV, filibuvir monotherapy or in combination with pegylated IFNα2a/ribavirin for up to 4 weeks significantly reduced HCV RNA levels compared with placebo or SoC alone.
Abstract: Filibuvir (PF-868554), being developed by Pfizer, is an orally administered, non-nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase for the potential treatment of chronic HCV infection. An estimated 180 million people worldwide are infected with HCV and at risk of developing chronic liver diseases that can lead to cirrhosis or hepatocellular carcinomas. HCV infection is the main cause of liver transplantation in industrialized nations. Filibuvir is a potent and specific inhibitor of the virally-encoded NS5B polymerase, and inhibited genotype 1 subgenomic HCV replication in the cell-based replicon system. Filibuvir demonstrated a good pharmacokinetic profile and oral bioavailability in preclinical animal studies, which is consistent with twice-daily dosing in humans. In phase I and a IIa clinical trial in treatment-naive patients infected with genotype 1 HCV, filibuvir monotherapy or in combination with pegylated IFNα2a/ribavirin (the standard of care [SoC] for HCV infection) for up to 4 weeks significantly reduced HCV RNA levels compared with placebo or SoC alone. The incidence and severity of adverse events were similar to SoC and placebo. At the time of publication, phase I pharmacokinetic clinical trials were ongoing in healthy volunteers and a phase IIb clinical trial was assessing filibuvir in combination with SoC for up to 24 weeks in treatment-naive patients infected with genotype 1 HCV. Results of this trial will help to characterize the potential of this drug class for the treatment of HCV infections.
11 citations
Patent•
16 Sep 2010
TL;DR: In this paper, the hepatitis C virus NS5B polymerase was used as an inhibitor of formula I: (I) wherein X, R 2, R 3, R 5 and R 6 were defined.
Abstract: Compounds of formula I: (I) wherein X, R 2 , R 3 , R 5 and R 6 are defined herein, are useful as inhibitors of the hepatitis C virus NS5B polymerase.
4 citations
3 citations
TL;DR: A range of 2-haloindole derivatives couples smoothly towards the nitrogen of various heterocycles as mentioned in this paper, and they are known as 2-Haloindoles (2H) derivatives.
Abstract: A range of 2-haloindole derivatives couples smoothly towards the nitrogen of various heterocycles.
1 citations