Enantiomerically pure adamantane carboxamides for the treatment of filovirus infection
Inventors
Plewe, Michael Bruno • McCormack, Kenneth • Henkel, Gregory • Sokolova, Nadezda V. • Brown, Eric • Gantla, Vidyasagar Reddy
Assignees
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Publication Number
US-11548893-B2
Publication Date
2023-01-10
Expiration Date
Abstract
The compounds of the invention as shown by general structure I, as shown below, are effective in treating filovirus infections.X is selected from the group consisting of O and H;R1 is selected from (C6 to C10) aryl and (C2 to C9) heteroaryl, andR2 is selected from (C1 to C10) alkyl, (C1 to C10) alkenyl, (C1 to C10) alkynyl, (C3 to C10) cycloalkyl, and (C5 to C10) cycloalkenyl, andNR3aR3b is defined in the specification.These compounds are effective in treating filovirii infections including Ebolavirus and Marburg virus.
Core Innovation
The invention relates to compounds of Structural Formula I, including compounds of Structural Formula Ia and Structural Formula Ib, and pharmaceutically acceptable salts, carriers, diluents, or vehicles thereof. The compounds are defined by extensive substituent selections involving R1, R2, NR3aR3b, Z, and multiple optional substituent positions, together with optional substitution and ring-closure rules involving N, O, and S heteroatoms within cycloheteroalkyl rings.
The invention further provides methods of treating infections associated with viruses of the Filoviridae enveloped virus, or any virus expressing filovirus glycoproteins to mediate cell entry. The method comprises administration of a therapeutically effective amount of a compound of Structural Formula I or a pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier, diluent, or vehicle, and includes enantiomerically pure embodiments represented by Structural Formula Ia or Structural Formula Ib.
Additional embodiments refine the treatment to infections associated with Ebolavirus and Marburgvirus and specify inhibition of the viral glycoprotein for the selected filovirus. The disclosed subject matter also includes co-administration with therapeutic agents, enumerating ribavirin; viral RNA-dependent-RNA polymerase inhibitors such as favipiravir, triazavirin, and remdesivir (GS-5734); monoclonal antibody therapies including ZMapp, REGN3470-3471-3479, and mAb 114; vaccines including cAd3-EBOZ and rVSV-ZEBOV; small interfering RNAs and microRNAs; and immunomodulators.
Claims Coverage
The consolidated claim coverage includes independent claim families directed to treating Filoviridae infections using Structural Formula I, Structural Formula Ia, and Structural Formula Ib compounds, as well as independent compound claims defining Structural Formula I and enantiomerically pure Structural Formula Ia/Ib variants. Across these claims, the inventive features are concentrated in treatment by administration of structurally defined compounds and in extensive substituent-definition constraints, with dependent refinements to specific filoviruses and glycoprotein inhibition.
Treatment of Filoviridae infections with Structural Formula I compounds
A method of treating infections associated with viruses of the Filoviridae enveloped virus, or any virus expressing filovirus glycoproteins to mediate cell entry, by administration of a therapeutically effective amount of a compound of Structural Formula I or a pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier, diluent, or vehicle, with R1 is phenyl and R2 selected from defined alkyl/alkenyl/alkynyl/cycloalkyl/cycloalkenyl options and further structural-variable constraints.
Treatment using enantiomerically pure Structural Formula Ia compounds
A method of treating infections associated with viruses of the Filoviridae enveloped virus, or any virus expressing filovirus glycoproteins to mediate cell entry, by administration of a therapeutically effective amount of an enantiomerically pure compound of Structural Formula Ia or a pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier, diluent, or vehicle, with R1 selected from aryl and heteroaryl options and R2 selected from defined alkyl/alkenyl/alkynyl/cycloalkyl/cycloalkenyl options and further structural-variable constraints.
Treatment using Structural Formula Ib compounds
A method of treating infections associated with viruses of the Filoviridae enveloped virus, or any virus expressing filovirus glycoproteins to mediate cell entry, by administration of a therapeutically effective amount of a compound of Structural Formula Ib or a pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier, diluent, or vehicle, with R1 selected from aryl and heteroaryl options and R2 selected from defined alkyl/alkenyl/alkynyl/cycloalkyl/cycloalkenyl options and further structural-variable constraints.
Compound represented by Structural Formula I
A compound represented by Structural Formula I or a pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier, diluent, or vehicle, defined by R1 is phenyl, R2 selection, NR3aR3b selection through Z, and additional R-group and ring-heteroatom constraints.
Enantiomerically pure compounds of Structural Formula Ia
An enantiomerically pure compound represented by Structural Formula Ia or a pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier, diluent, or vehicle, defined by R1, R2, NR3aR3b through Z, and additional R-group and ring-heteroatom constraints.
Enantiomerically pure compounds of Structural Formula Ib
An enantiomerically pure compound represented by Structural Formula Ib or a pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier, diluent, or vehicle, defined by R1, R2, NR3aR3b through Z, and additional R-group and ring-heteroatom constraints.
Compound selected from a group of alternative compounds
A compound selected from the group consisting of compounds presented in the claim.
The independent claims collectively cover treatment of Filoviridae-associated infections, including viruses expressing filovirus glycoproteins to mediate cell entry, by administering structurally defined Structural Formula I, Ia, or Ib compounds, including enantiomerically pure embodiments. The structural coverage is implemented through detailed substituent selections and ring constraints, with dependent refinements narrowing target filoviruses and, in some embodiments, requiring inhibition of the viral glycoprotein.
Stated Advantages
Inhibits Filoviridae entry and native virus replication.
Provides surprising enantiomer-dependent potency differences.
Validates activity against native BSL-4 Ebola/Sudan viruses.
Shows drug-like property characterization including microsome stability, CYP450 and hERG, solubility, and Caco-2 permeability with P-gp efflux assessment.
Supports suitability for in vivo treatment, including mouse pharmacokinetics comparison to favipiravir.
Documented Applications
Therapeutic treatment of infections associated with viruses of the Filoviridae enveloped virus, including inhibition of virus entry mediated by filovirus glycoproteins.
Treatment of infections associated with Ebolavirus and Marburgvirus within Filoviridae.
Validation of antiviral activity against native BSL-4 Ebola/Sudan viruses using plaque reduction and viral yield reduction assays.
Use of VSV pseudotype system with filovirus glycoproteins for screening filovirus entry inhibitors and cytotoxicity/dose-response evaluation.
In vivo suitability assessment supported by mouse pharmacokinetics for an example compound (A2).
Use of kit concepts for formulations comprising a container with an inhibitor and instructions for mixing and administration, including oral formulation, inhaler, and intravenous injection concepts.
Use of a pseudotype-based inhibitory testing workflow to assess inhibition using VSV-Luc pseudotypes bearing various filovirus glycoproteins, including a comparative test against native VSV to distinguish effects on filovirus entry from effects on the parent VSV.
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