Oleic acid derivatives as treatments for Friedreich ataxia and inhibitors of ferroptosis
Inventors
Smith, Amos • Wilson, Robert B. • Huryn, Donna M • Cotticelli, Maria Grazia • XIA, Shujuan • Lee, Taehee • Forestieri, Roberto
Assignees
Childrens Hospital of Philadelphia CHOP • University of Pennsylvania Penn
Publication Number
US-12378178-B2
Publication Date
2025-08-05
Expiration Date
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Abstract
The invention relates to compounds of Formula I or Formula II: to compositions comprising such compounds, and to methods of use thereof for treating neurodegenerative disorders, such as Friedreich ataxia.
Core Innovation
The invention relates to compounds of Formula I or Formula II, to compositions comprising such compounds, and to methods of use thereof for treating neurodegenerative disorders, such as Friedreich ataxia, and for inhibiting ferroptosis. In one embodiment, provided herein is a compound represented by Formula I or Formula II wherein R is H or C1-C6 alkyl; m is an integer from 1 to 10; n is an integer from 1 to 10; and Y is CF3 or CCl3, or a prodrug or optical isomer thereof, and pharmaceutical compositions and methods of administration comprising such compounds are provided.
Friedreich ataxia (FRDA) is an autosomal recessive neuro- and cardio-degenerative disorder characterized by progressive gait and limb ataxia, dysarthria, areflexia, and sensory loss, and currently there is no cure or FDA approved treatment available for FRDA patients. Recently, studies have linked neurodegeneration to ferroptosis, a pathway that can be triggered by iron overload and that leads to cell death through lipid peroxidation, and the disclosure identifies oleic acid derivatives and related compounds as agents for inhibiting ferroptosis and treating FRDA and other neurodegenerative diseases.
Claims Coverage
This patent includes two independent claims directed to (1) a compound of defined structural Formula I and (2) a method of treating Friedreich ataxia by administering a compound of a specified formula. The main inventive features are extracted below.
Compound of Formula I
A compound represented by Formula I (or Formula II) wherein R is H or C1-C6 alkyl; m is an integer from 1 to 10; n is an integer from 1 to 10; Y is CF3 or CCl3; and the compound may be a prodrug or optical isomer thereof.
Method of treating Friedreich ataxia by administering specified compound
A method of treating Friedreich ataxia in a subject comprising administering to the subject an effective amount of a compound having the specified formula (a compound of the invention) or a pharmaceutical composition thereof.
The independent claims cover (a) the chemical composition defined by Formula I/II with specified substituents and isomeric/prodrug embodiments, and (b) the therapeutic method of administering such a compound to treat Friedreich ataxia.
Stated Advantages
Compounds and compositions for treating neurodegenerative disorders, such as Friedreich ataxia.
Compounds and compositions for inhibiting ferroptosis.
Efficacy in cellular models of Friedreich ataxia and ferroptosis (e.g., OA200R identified as efficacious in cellular models).
Provides compounds and methods intended to address the need for improved therapies for neurodegenerative diseases.
Documented Applications
Treating neurodegenerative diseases, including Friedreich ataxia.
Inhibiting ferroptosis in a subject.
Treating neurodegenerative brain disorders selected from Parkinson's disease, Huntington's disease and Alzheimer's disease.
Treating disorders in which ferroptosis plays a role, including carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemic-reperfusion injury and kidney degeneration.
Use in pharmaceutical compositions formulated for various routes of administration and dosage forms.
Potential application in diseases such as liver hemochromatosis and other conditions where ferroptosis is implicated.
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