Antiviral compounds and methods of use thereof
Inventors
GUENTHER, Richard H. • Szewczyk, Jerzy R.
Assignees
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Publication Number
US-10098887-B2
Publication Date
2018-10-16
Expiration Date
Abstract
Inhibitors of retroviral propagation, methods of treatment and prevention of retroviral infections using the inhibitors, and pharmaceutical compositions including the inhibitors, are disclosed.
Core Innovation
The invention relates to antiviral inhibitor chemical series directed to retroviral propagation, including compounds defined by general scaffold formulas and their variants. The disclosed structures define structural variables and substituent options across multiple formulas and provide representative compound structures fitting these scaffolds.
The disclosure frames mechanism concepts at a high level in connection with retroviral reverse transcription and tRNA-related processes. The inhibitors are described as acting in a way that involves recruitment and/or primer binding and packaging inhibition, with reference to tRNA(Lys3) recruitment and the tRNA anticodon stem loop, and the document connects the chemical series to inhibition of retroviral propagation.
The patent also describes synthetic steps for protected ribonucleosides and conversion to phosphoramidite intermediates bearing 2′-O-TBDMS protection and 5′-DMT, together with nucleoside protecting-group approaches and RNA solid-phase synthesis workflow. It further describes an HIV inhibitor screening workflow using immobilized RNA-TNA complex assays and AlphaScreen proximity assays, followed by downstream anti-HIV cytoprotection in CEM-SS cells with MTS readout.
Claims Coverage
The consolidated independent claims provide four main inventive feature sets. Each claim is centered on a pharmaceutical composition that combines a disclosed retroviral-propagation inhibitor scaffold, either a defined formula or Formula H, with a pharmaceutically acceptable carrier and an additional antiviral agent selected from defined antiviral classes; the other claim set covers formula-defined compounds with specified RNA-related assay context in the disclosure.
Pharmaceutical composition with formula compound and additional antiviral agent
A pharmaceutical composition comprising a compound of the following formula, wherein R4, R5, R6, R7, R15, R16, and R17 are, independently, the same or different, and are selected from the group consisting of hydrogen, C1-C6 alkyl, piperidinyl, phenyl, naphthyl, C2-6 alkenyl, and halo, and a pharmaceutically-acceptable carrier, and further comprising an additional antiviral agent selected from the group consisting of entry inhibitors, integrase inhibitors, reverse transcriptase inhibitors, and immune-based therapeutic agents.
Pharmaceutical composition with Formula H compound and additional antiviral agent
A pharmaceutical composition comprising a compound of Formula H, wherein R4, R5, R6, R7, R15, R16, and R17 are, independently, the same or different, and are selected from the group consisting of hydrogen, C1-C6 alkyl, piperidinyl, phenyl, naphthyl, C2-C6 alkenyl, and halo, and further comprising an additional antiviral agent selected from the group consisting of entry inhibitors, integrase inhibitors, reverse transcriptase inhibitors, and immune-based therapeutic agents.
The claim coverage focuses on pharmaceutical compositions containing a formula-defined compound, including Formula H, combined with an additional antiviral agent from defined antiviral classes; one claim scope also includes a pharmaceutically acceptable carrier.
Stated Advantages
The disclosure relates to antiviral activity, including retroviral propagation inhibition and reverse transcription inhibition.
It discusses antiviral formulations and combination therapy contexts.
It includes assay and screening context with measured readouts such as CPE reduction and IC50 values, as well as cytotoxicity and cytoprotection assay concepts.
Documented Applications
Retroviral propagation inhibition, including reverse transcription inhibition, and related treatment or prevention of retroviral infection using the disclosed compositions.
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