Compound modulating GSK-3 activity
Inventors
Gupta, Sarika • Siddiqui, Ibrar Ahmed • Nilakhe, Aishwarya • Upadhyay, Prabhat
Assignees
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Publication Number
US-11820764-B2
Publication Date
2023-11-21
Expiration Date
Abstract
The present invention provides a novel compound of formula I, its derivatives, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for modulating GSK3 level (e.g., GSK3 (e.g., GSK3a/GSK3b or GSK3P) or CK1) hence, activity.
Core Innovation
The disclosure provides a novel indole-containing compound of formula I and derivatives thereof, including pharmaceutically acceptable salts. An example compound is 6-(5-ethylidene-4-oxo-2thioxo-thiazolidin-3-yl)-hexanoic acid with 1H-indole. The compounds are described as being suitable for pharmaceutical compositions.
The formula I compounds induce in vivo and/or in situ downregulation of GSK-3α and GSK-3β. This downregulation is described as autophagy-dependent degradation, and the disclosure optionally includes CK1.
Treatment with the formula I compounds improves Alzheimer’s-related behavioral deficits in 5×FAD transgenic mice. The disclosure describes experimental evidence including time-dependent GSK-3 downregulation, absence of toxicity at tested doses, blood-brain barrier penetration by CSF detection, pharmacokinetics, enhanced autophagy markers such as LC3B-II, reduced amyloid/tau pathology including Aβ42 plaques and tau aggregates, and restored acetylcholine and inflammatory/microglial/astrocyte markers in treated animals.
Claims Coverage
The independent claim covers a treatment method that includes administering a specific formula I indole-containing compound and determining modulation of GSK-3 activity in the subject, with the modulation including downregulation. The disease scope is selected from chronic neurodegenerative diseases of Alzheimer’s disease, psychiatric disorders, metabolic disorders, or cancer.
Administering a formula I indole-containing compound for treating a GSK-3 mediated disease
Administering, to a subject, a compound of formula I or its pharmaceutically acceptable salts, where the compound is 6-(5-ethylidene-4-oxo-2thioxo-thiazolidin-3-yl)-hexanoic acid with 1H-indole.
Determining modulation of GSK-3 activity in the subject
Determining, based on administration of the compound of formula I, modulation of GSK-3 activity of the subject, where the GSK-3 mediated disease is selected from chronic neurodegenerative diseases of Alzheimer’s disease, psychiatric disorders, metabolic disorders or cancer.
Downregulation of GSK-3 activity
The modulation includes downregulation of GSK-3 activity.
Overall, the claim coverage centers on a method of treating a GSK-3 mediated disease by administering the specific formula I indole-containing compound or its pharmaceutically acceptable salts and determining that GSK-3 activity is modulated in the subject, with modulation including downregulation, for diseases selected from the specified categories.
Stated Advantages
Induces in vivo and/or in situ downregulation of GSK-3α and GSK-3β via autophagy-dependent degradation.
Improves Alzheimer’s-related behavioral deficits in 5×FAD transgenic mice.
Increases autophagy markers such as LC3B-II.
Reduces amyloid/tau pathology including Aβ42 plaques and tau aggregates.
Restores acetylcholine and inflammatory/microglial/astrocyte markers in treated animals.
Demonstrates blood-brain barrier penetration as indicated by CSF detection.
Documented Applications
Treating a GSK-3 mediated disease, selected from chronic neurodegenerative diseases of Alzheimer’s disease, psychiatric disorders, metabolic disorders, or cancer.
Alzheimer’s-related treatment in 5×FAD transgenic mice, including improvement of Alzheimer’s-related behavioral deficits.
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