The hepatitis C viral proteins NS3/4A protease, NS5B polymerase, and NS5A are clinically validated targets for direct-acting antiviral therapies. The NS5B polymerase may be inhibited directly through ...the action of nucleosides or nucleotide analogues or allosterically at a number of well-defined sites. Herein we describe the further development of a series of thiophene carboxylate allosteric inhibitors of NS5B polymerase that act at the thumb pocket 2 site. Lomibuvir (1) is an allosteric HCV NS5B inhibitor that has demonstrated excellent antiviral activity and potential clinical utility in combination with other direct acting antiviral agents. Efforts to further explore and develop this series led to compound 23, a compound with comparable potency and improved physicochemical properties.
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Inhibitors of the HCV NS5A nonstructural protein are showing promising clinical potential in the treatment of hepatitis C when used in combination with other direct-acting antiviral ...agents. Current NS5A clinical candidates such as daclatasvir, ledipasvir, and ombitasvir share a common pharmacophore that features a pair of (S)-methoxycarbonylvaline capped pyrrolidines linked to various cores by amides, imidazoles and/or benzimidazoles. In this Letter, we describe the evaluation of NS5A inhibitors which contain alternative heteroaromatic replacements for these amide mimetics. The SAR knowledge gleaned in the optimization of scaffolds containing benzoxazoles was parlayed toward the identification of potent NS5A inhibitors containing other heteroaromatic replacements such as indoles and imidazopyridines.
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The treatment of HCV with highly efficacious, well-tolerated, interferon-free regimens is a compelling clinical goal. Trials employing combinations of direct-acting antivirals that ...include NS5A inhibitors have shown significant promise in meeting this challenge. Herein, we describe our efforts to identify inhibitors of NS5A and report on the discovery of benzimidazole-containing analogs with subnanomolar potency against genotype 1a and 1b replicons. Our SAR exploration of 4-substituted pyrrolidines revealed that the subtle inclusion of a 4-methyl group could profoundly increase genotype 1a potency in multiple scaffold classes.
Further SAR studies on the thiophene-2-carboxylic acids are reported. These studies led to the identification of a series of tertiary amides that show inhibition of both HCV NS5B polymerase in vitro ...and HCV subgenomic RNA replication in Huh-7 cells. Structural insights about the bioactive conformation of this class of molecules were deduced from a combination of modeling and transferred NOE (trNOE) studies.
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The discovery of a novel class of HCV NS5B polymerase inhibitors, 3-arylsulfonylamino-5-phenyl-thiophene-2-carboxylic acids is described. SAR studies have yielded several potent inhibitors of HCV ...polymerase as well as of HCV subgenomic RNA replication in Huh-7 cells.
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Various 2-substituted-
N-benzyl-4,4,7-trimethyl-
trans-octahydro-1,3-benzoxazines
2 were prepared from the condensation of (−)-8-benzylaminomenthol
1 derived from (+)-pulegone, with acrolein, ...crotonaldehyde, cinnamaldehyde, 2(
E)-
N,
N-diisopropyl-4-oxobut-2-enamide, ethyl (2
E)-4-oxobut-2-enoate, and 2-furaldehyde in 71–96% yield. The 1,3-dipolar cycloaddition with aceto- and benzonitrile oxide gave the corresponding 2-isoxazoline cycloadducts. The origin of the stereoselectivity (4′
S, 5′
S-cycloadducts up to 64% de) arises from the cycloaddition of the dipole to the top of the
Re,Re-alkene face of dipolarophile
2.
The HCV NS5B RNA dependent RNA polymerase plays an essential role in viral replication. The discovery of a novel class of inhibitors based on an N,N-disubstituted phenylalanine scaffold and ...structure−activity relationships studies to improve potency are described.
Herein, we describe the structure–activity relationship (SAR) of
N,N-disubstituted phenylalanine series of NS5B polymerase inhibitors of hepatitis C. The NS5B polymerase inhibitory activity of the ...most active compound exhibited an IC
50 of 2.7 μM.
The structure–activity relationship (SAR) of NS5B polymerase inhibitor (
1) with an IC
50 of 3.5 μM is reported.
HCV NS5B RNA-dependent RNA polymerase (NS5B) is essential for viral replication and is therefore considered a target for antiviral drug development. From our ongoing screening effort in the search ...for new anti-HCV agents, a novel inhibitor 1 with low microM activity against the HCV NS5B polymerase was identified. SAR analysis indicated the optimal substitution pattern required for activity, for example, carboxylic acid group at 2-position of thiophene ring. We describe the steps taken to identify and solve the bioactive conformation of derivative 6 through the use of the transferred NOE method (trNOE).
