CRM1 inhibitors for treating epilepsy
Inventors
Tamir, Sharon • Lee, Margaret • De Ryck, Marc • Kaminski, Rafal M. • Leclercq, Karine • Kenda, Benoit
Assignees
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Publication Number
US-11602530-B2
Publication Date
2023-03-14
Expiration Date
Abstract
The invention generally relates to the use of nuclear transport modulators, e.g., CRM1 inhibitors, of Formula (I) for treating epilepsy in a subject. Subjects can have unprovoked seizures without prior warning that affect one or both hemispheres of the brain. The disclosed methods can reduce the severity and occurrence of these unprovoked epileptic seizures and can result in resolution of epilepsy. The method comprises administering to the subject an effective amount of a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof.
Core Innovation
The invention relates to nuclear transport modulator (CRM1/exportin-1) inhibitors of Formula (I) for treating epilepsy. The compounds include structural options including Y (O or S) and substitution variables at the R8 position, with R8 defined by substituted cycloalkyl, heterocyclyl, or heteroaryl groups and with optional N-alkyl or oxo substitution. The disclosed structures are provided as representative compounds E-1 to E-15, including compound E-1 (KPT-350), for use as CRM1/exportin-1 inhibitors.
The problem addressed is the treatment of epilepsy in a subject, including unprovoked partial or generalized seizures, with relevance to both convulsive and non-convulsive seizure presentations. The document describes treatment goals focused on reducing seizure severity and/or seizure frequency, with the potential for resolution. The disclosure also links CRM1 inhibition to nuclear export of multiple regulatory proteins.
CRM1 inhibition is described as affecting nuclear export of regulatory proteins including p53, c-Abl, p21, p27, pRB, BRCA1, IkB, E2F4, KLF5, YAP1, FOXO3a, HDAC4, and HDAC5. The document further describes in vivo evaluation in a pilocarpine model of temporal lobe epilepsy (TLE), where compound E-1 (KPT-350) reduced seizure activity in treated animals without body-weight change, as described in the provided example.
Claims Coverage
The independent claim covers one broad inventive concept: treating epilepsy by administering a CRM1/exportin-1 inhibitor compound from a specified list (E1–E15) or a pharmaceutically acceptable salt, hydrate, or solvate. The dependent claims refine the specific compound selection within that same list and also specify acceptable solid forms.
Treating epilepsy by administering a CRM1/exportin-1 inhibitor selected from E1–E15
A method of treating a subject suffering from epilepsy comprising administering to the subject a compound selected from E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, and E15.
Selection of illustrated compound and acceptable salt, hydrate, or solvate forms
The method wherein the compound is selected to be a specific illustrated compound and the method includes a pharmaceutically acceptable salt, hydrate, or solvate thereof.
Across the independent and dependent coverage, the core inventive scope is administration of a disclosed Formula (I) CRM1/exportin-1 inhibitor from the enumerated E1–E15 set and acceptable salt, hydrate, or solvate forms for treating epilepsy.
Stated Advantages
Reducing seizure severity and/or seizure frequency in epilepsy.
Potential resolution of seizure activity.
In a pilocarpine model of temporal lobe epilepsy, compound E-1 (KPT-350) reduced seizure activity without body-weight change.
Documented Applications
Treating a subject suffering from epilepsy, including unprovoked partial or generalized seizures (convulsive and non-convulsive).
Evaluation in a pilocarpine model of temporal lobe epilepsy (TLE).
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