Benzodioxane modulators of leukotriene A4 hydrolase (LTA4H) for prevention and treatment of aging-associated diseases
Inventors
Campbell, Meghan Kerrisk • Czirr, Eva • Harish, Reema
Assignees
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Publication Number
US-11957671-B2
Publication Date
2024-04-16
Expiration Date
Abstract
This invention pertains to the prevention and treatment of aging-associated disease. The invention relates to the use of benzodioxane inhibitors of leukotriene production through modulation of leukotriene A4 hydrolase (“LTA4H”) to treat and/or prevent conditions associated with aging such as cognitive disorders, motor disorders, and neuroinflammation.
Core Innovation
The invention concerns a method of improving cognitive function in a subject diagnosed with an age-related cognitive disease by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compounds of formula (I) are defined by variables including X, n, R1, R2, R3, a nitrogen-containing heterocyclic ring system designated as A with ring B, an optional linker L, and substituents R6 and R7.
In formula (I), X is N or CH, n is an integer from 0 to 3, and R1 is selected from halo, OH, CN, (C1-C6)alkyl, O(C1-C6)alkyl, and (C3-C6)cycloalkyl. R2 and R3 are each independently H or (C1-C6)alkyl, and R2 and R3 may join to form a 3- to 6-membered ring optionally having from one to three heteroatoms and optional substitution.
Ring A is a (4- to 14-membered) N-heterocyclic ring, and ring B is a non-aromatic 4-8 membered monocyclic radical or a bridged bicyclic radical, a spirocyclic radical, or a 6 to 11-membered fused bicyclic radical. At least a nonaromatic N-heterocyclic ring of each bridged bicyclic radical, spirocyclic radical, or fused bicyclic radical is attached to carbon atom 1, L is absent or a (C1-C6)alkylene linker, and one or more additional active agents may be administered.
Claims Coverage
The consolidated claim coverage centers on one independent claim for improving cognitive function in a subject diagnosed with an age-related cognitive disease by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, with one or more additional active agents optionally included. The claim is defined by multiple inventive features spanning X, n, R1-R3, ring system A/ring B, linker L, and R6/R7.
Therapeutically effective administration of formula (I) for cognitive improvement
A method of improving cognitive function in a subject diagnosed with an age-related cognitive disease by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, optionally with one or more additional active agents.
Defined formula (I) variable scaffold
X is N or CH; n is an integer from 0 to 3; R1 is selected from halo, OH, CN, (C1-C6)alkyl, O(C1-C6)alkyl, and (C3-C6)cycloalkyl; and R2 and R3 are each independently H or (C1-C6)alkyl, with R2 and R3 optionally joining to form a 3- to 6-membered ring optionally having from one to three heteroatoms and optional substitution.
N-heterocyclic ring A with defined ring B topology
A is a (4- to 14-membered) N-heterocyclic ring in which ring B is a non-aromatic 4-8 membered monocyclic radical or a bridged bicyclic radical, a spirocyclic radical, or a 6 to 11-membered fused bicyclic radical, and at least a nonaromatic N-heterocyclic ring of each bridged bicyclic radical, spirocyclic radical, or fused bicyclic radical is attached to carbon atom 1; ring B may additionally contain N, O, and S and may be optionally substituted.
Optional linker L and defined R6/R7 substituent framework
L is absent or a (C1-C6)alkylene linker; each R6 is independently selected from defined halo, OR7, CF3, CN, alkyl, alkoxy, cycloalkyl, carbonyl, amide, sulfonyl, aryl, heteroaryl, and heterocycloalkyl classes with optional substitution; and each R7 is independently selected from H and defined alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups with optional substitution.
The inventive scope is centered on administering defined formula (I) compounds for cognitive improvement in age-related cognitive disease, with the main limitations provided by the formula (I) scaffold, the ring A/ring B topology attached to carbon atom 1, the optional linker L, and the R6/R7 substituent definitions.
Stated Advantages
Improving cognitive function in a subject diagnosed with an age-related cognitive disease.
One or more additional active agents may be administered.
Improves contextual/spatial memory in aged mice across multiple cohorts and timepoints.
Reduces astrocyte reactivity markers, including GFAP, and reduces BBB-associated AQP4 with earlier onset.
Improves BBB leakage response in an LPS-induced BBB breakdown model.
Enhances neurovascular unit/perivascular markers, including pericyte coverage and reduced albumin/fibrinogen leak.
Produces broad beneficial gene expression shifts across endothelial, astrocyte, pericyte, and neuronal populations.
Increases long-term potentiation (LTP).
Shows unexpectedly robust cognitive improvements in aged mice and/or neuroinflammation models.
Documented Applications
Use in a method of improving cognitive function in a subject diagnosed with an age-related cognitive disease.
Application to CADASIL.
Treating cognitive impairment in the context of aging-associated diseases.
Treating motor disorders, including Parkinson’s disease.
Treating neuroinflammation and neurodegenerative disease.
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