Methods of treating neurological disorders
Inventors
Dransfield, Paul • Fernando, Dilinie • Harvey, James • SPARLING, Brian • Stellwagen, John • Ma, Zhihua • Beausoleil, Anne-Marie • Hudson, Ryan
Assignees
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Publication Number
US-11993580-B1
Publication Date
2024-05-28
Expiration Date
Abstract
The present disclosure relates to compounds of Formula (I),and pharmaceutically acceptable salts thereof, wherein the variable are as described herein, and compositions and uses of same for treating neurological disorders.
Core Innovation
The disclosure relates to Formula (I) compounds identified as CK-1δ inhibitors, including pharmaceutically acceptable salts and example pyrimidin-4(3H)-one derivatives within Formula (I). The disclosure defines variant forms for Formula (I), including stereoisomers, tautomers, isotopic forms, and sub-formulas (I-A through I-D), with variable substituent definitions within the Formula (I)/(I-D) structures.
The invention links CK-1δ (CSNK1D) to pathological phosphorylation of TDP-43, including Ser409/410 markers, and describes inhibition of CK-1δ as associated with inhibiting TDP-43 phosphorylation and TDP-43 aggregation. The methods include inhibiting CK-1δ and inhibiting TDP-43 phosphorylation in cells by contacting cells with a Formula (I) compound or a pharmaceutically acceptable salt thereof.
The disclosed compounds and compositions are described for treating CK-1δ-associated neurological disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, frontotemporal dementia (FTD), FTLD-U, and limbic-predominant age-related TDP-43 encephalopathy (LATE). Specific Formula (I) compounds are exemplified, including Compound 1, Compound 2, and related compounds such as Compound 3.
Claims Coverage
The independent claims cover three specific Formula (I) CK-1δ inhibitor compounds, each recited as a fixed pyrimidin-4(3H)-one structure or a pharmaceutically acceptable salt thereof. The claim coverage centers on these exact named chemical structures, with no additional functional or process limitations beyond the salt form.
Specific pyrimidin-4(3H)-one CK-1δ inhibitor compound
A compound having the structure of 5-(4-chlorophenyl)-2-isobutyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.
Specific methylamino pyrimidin-4(3H)-one CK-1δ inhibitor compound
A compound having the structure of 5-(4-chlorophenyl)-3-methyl-2-(methylamino)-6-(pyridin-4-yl)pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.
Specific chloro-fluoro pyrimidin-4(3H)-one CK-1δ inhibitor compound
A compound having the structure of 5-(4-chloro-2-fluorophenyl)-2-isobutyl-6-(2-methylpyridin-4-yl)pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.
Across the independent claims, the inventive coverage is directed to defined pyrimidin-4(3H)-one CK-1δ inhibitor compounds, each fixed to a specific named chemical structure and corresponding pharmaceutically acceptable salts.
Stated Advantages
Enables treating CK-1δ-associated neurological disorders including ALS, Alzheimer’s disease, FTD, FTLD-U, and LATE.
Inhibits CK-1δ and inhibits TDP-43 phosphorylation associated with Ser409/410 markers.
Inhibits TDP-43 aggregation.
Provides pharmaceutical compositions including pharmaceutically acceptable salts for a therapeutically effective amount.
Documented Applications
Inhibiting CK-1δ activity in cells by contacting with a Formula (I) compound or a pharmaceutically acceptable salt thereof.
Inhibiting TDP-43 phosphorylation and inhibiting TDP-43 aggregation in cells containing TDP-43 and CK-1δ.
Treatment of CK-1δ-associated neurological disorders, including amyotrophic lateral sclerosis (ALS).
Treatment of CK-1δ-associated neurological disorders, including Alzheimer’s disease.
Treatment of CK-1δ-associated neurological disorders, including frontotemporal dementia (FTD).
Treatment of CK-1δ-associated neurological disorders, including FTLD-U.
Treatment of CK-1δ-associated neurological disorders, including limbic-predominant age-related TDP-43 encephalopathy (LATE).
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