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Publication Number
US-10851084-B2
Publication Date
2020-12-01
Expiration Date
Abstract
The new piperazine derivatives are modulators of TRPML and are useful in treating disorders related to TRPML activities such as lysosome storage diseases, muscular dystrophy, age-related common neurodegenerative diseases, oxidative stress or reactive oxygen species (ROS) related diseases, and ageing.
Core Innovation
The document describes piperazine-based TRPML modulator compounds, with emphasis on TRPML1. It provides a TRPML modulator chemical scaffold defined as Formula I, including compounds and their salts, solvates, hydrates, polymorphs, and prodrugs, and describes representative structures and example compounds consistent with the Formula I scaffold.
The background links lysosomal TRPML1 to lysosomal trafficking defects, oxidative stress and ROS regulation, and ageing and photoaging. The document positions TRPML agonism as a therapeutic strategy to treat or lessen TRPML-mediated disorders, including lysosome storage diseases, and conditions associated with impaired lysosomal trafficking and related cellular processes.
The described subject matter also includes TRPML1 agonist compounds and their use in biological settings to evaluate cellular responses. It connects TRPML1 agonist activity to TFEB nuclear translocation, lysosome-associated readouts, lysosomal Ca2+ imaging, endolysosomal electrophysiology, and ROS-associated measurements.
Claims Coverage
The independent claim set includes three main independent claims: one for a chemical compound genus defined by Formula I, and two for therapeutic methods centered on TRPML1 agonism for oxidative stress or ROS-related diseases and anti-ageing use. Across these, the claims cover a defined structural family with multiple substituent ranges and specific therapeutic use as TRPML1 agonists.
Formula I TRPML1 modulator compound family
A compound of formula I, including salts, prodrugs, hydrates, solvates, or polymorphs, with independently defined X, Y, Ary, and R1-R9 substituents and a defined exclusion set.
Treating oxidative stress or ROS-related diseases using TRPML1 agonists
Administering an effective amount of a TRPML1 agonist, or a composition comprising a TRPML1 agonist, to a subject with oxidative stress or reactive oxygen species-related diseases or disease symptoms.
TRPML1 agonist as an anti-ageing agent
Using a TRPML1 agonist as an anti-ageing agent.
Overall claim coverage centers on a Formula I piperazine-based TRPML modulator and method claims that use TRPML1 agonists to treat oxidative stress or ROS-related diseases and to function as anti-ageing agents.
Stated Advantages
Treatment of oxidative stress or reactive oxygen species (ROS) related diseases or disease symptoms by administering a TRPML1 agonist.
Use of a TRPML1 agonist as an anti-ageing agent, including skin ageing and photo ageing.
Treatment of TRPML1-mediated loss-of-function diseases, including lysosome storage diseases such as Niemann-Pick C (NPC) and Mucolipidosis type IV (ML4).
Documented Applications
Treating oxidative stress or reactive oxygen species (ROS) related diseases or disease symptoms by administering an effective amount of a TRPML1 agonist or a composition comprising a TRPML1 agonist.
Using a TRPML1 agonist as an anti-ageing agent.
Treating skin ageing using a TRPML1 agonist or a composition containing it.
Treating photo ageing using a TRPML1 agonist or a composition containing it.
Treating TRPML1-mediated loss-of-function diseases, including Mucolipidosis type IV (ML4) and Niemann-Pick C (NPC).
Treating TRPML-mediated disorders by providing piperazine-based TRPML modulators, with emphasis on TRPML1.
Treating or lessening lysosome storage diseases and lysosomal trafficking defects linked to lysosomal TRPML1, including ML4 and ML1 loss-of-function contexts.
Assessing TRPML1 agonist activity using TFEB nuclear translocation assay, lysosomal Ca2+ imaging, and related ROS readouts.
Using TRPML1 agonist compounds in the context of endolysosomal electrophysiology and related lysosomal-associated functional measurements.
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