Compounds, compositions and methods
Inventors
Craig, II, Robert A. • de Vicente Fidalgo, Javier • Estrada, Anthony A. • Feng, Jianwen A. • Fox, Brian M. • Osipov, Maksim • Thottumkara, Arun
Assignees
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Publication Number
US-11958840-B2
Publication Date
2024-04-16
Expiration Date
Abstract
The present disclosure relates generally to eukaryotic initiation factor 2B modulators, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, and methods of making and using thereof.
Core Innovation
The invention relates to treating a disease or condition mediated, at least in part, by eukaryotic initiation factor 2B. The method comprises administering an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, to a subject in need thereof. The compounds are defined by ring A, ring B with Q1 and Q2, linker L, and substituent variables including z, X1, and R1 through R15, with Formula II also defining p and additional substituent groups.
The invention concerns eukaryotic initiation factor 2B (eIF2B) modulators in the form of small molecules for therapeutic use. The disclosed approach addresses diseases or conditions mediated, at least in part, by eIF2B, and the eIF2B effects are linked to downstream reduction of ATF4 expression and reduction of stress granule formation, within the integrated stress response (ISR) pathway. The disclosure also includes pharmaceutical composition and treatment method formats.
Formula I and Formula II include structural constraints in which ring A is C3-10 cycloalkyl or heterocyclyl, ring B contains Q1 and Q2 each independently O, S, or NR15, L is a C1-6 alkylene linker optionally substituted with one to three substituents, z is 0 or 1, and X1 is O, NR9, or a bond. The disclosure further includes multiple generic scaffold formulas, representative compounds, and example small-molecule scaffolds consistent with the Formula I/II frameworks.
Claims Coverage
The independent claim coverage centers on methods for treating diseases or conditions mediated, at least in part, by eukaryotic initiation factor 2B, by administering an effective amount of compounds of Formula I or Formula II, or selected compounds having a specified structure. The claims include extensive structural limitations on ring systems, linker L, heteroatom selections, and variable substituents, and the claimed treatment methods are directed to eIF2B-mediated disease indications.
Treatment of eIF2B-mediated disease by administering Formula I modulators
A method for treating a disease or condition mediated, at least in part, by eukaryotic initiation factor 2B, comprising administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, to a subject in need thereof, wherein ring A, ring B (Q1 and Q2), linker L, and the variable substituent groups are defined by the specified structural constraints.
Treatment of eIF2B-mediated disease by administering Formula II compounds
A method for treating a disease or condition mediated, at least in part, by eukaryotic initiation factor 2B, comprising administering an effective amount of a compound of Formula II, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, to a subject in need thereof, wherein p, ring B (Q1 and Q2), linker L, z, X1, and variable groups R1 through R15 are defined as specified.
Treatment of eIF2B-mediated disease by administering selected compounds
A method for treating a disease or condition mediated, at least in part, by eukaryotic initiation factor 2B, comprising administering an effective amount of a compound selected from the group consisting of the compounds recited in the claim, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, to a subject in need thereof.
Treatment of eIF2B-mediated disease with a specified compound structure
A method for treating a disease or condition mediated, at least in part, by eukaryotic initiation factor 2B by administering an effective amount of a compound having the structure recited in the claim, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
Overall, the claim coverage is directed to administering effective amounts of Formula I or Formula II compounds, or selected compounds having a specified structure, for treatment of eIF2B-mediated diseases, with the main inventive content centered on the defined chemical scaffold and its structural variables.
Stated Advantages
Activates eIF2B via increased eIF2B GDP/GTP exchange.
Promotes eIF2B dimerization.
Provides desensitization to eIF2B inhibition.
Reduces ATF4 expression downstream.
Reduces stress granule formation via the integrated stress response (ISR) pathway.
Documented Applications
Treating diseases or conditions mediated, at least in part, by eukaryotic initiation factor 2B, including Alexander's disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, Huntington's disease, frontotemporal dementia, ataxia telangiectasia, Batten disease, bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, insulin resistance, and other listed diseases or conditions.
Treatment of amyotrophic lateral sclerosis (ALS) is explicitly included in dependent claims that narrow the disease list.
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