4-(p-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases
Inventors
Jankowski, Orion D. • Wesson, Kieron E. • Mollard, Paul • Shrader, William D.
Assignees
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Publication Number
US-11840497-B2
Publication Date
2023-12-12
Expiration Date
Abstract
Methods of treating or suppressing mitochondrial diseases, such as Friedreich's ataxia (FRDA), Leber's Hereditary Optic Neuropathy (LHON), mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS), Kearns-Sayre Syndrome (KSS), are disclosed, as well as compounds useful in the methods of the invention, such as 4-(p-quinolyl)-2-hydroxybutanamide derivatives. Methods and compounds useful in treating other disorders such as amyotrophic lateral sclerosis (ALS), Huntington's disease, Parkinson's disease, and pervasive developmental disorders such as autism are also disclosed. Energy biomarkers useful in assessing the metabolic state of a subject and the efficacy of treatment are also disclosed. Methods of modulating, normalizing, or enhancing energy biomarkers, as well as compounds useful for such methods, are also disclosed.
Core Innovation
The disclosure provides redox-active 4-(p-quinonyl/quinolyl)-2-hydroxybutanamide derivative compounds according to Formula I and subformulas I-S/I-Saa/I-Sbb, including Formula Ia/Iaa and Formula Ib/Ibb. The compounds are provided with broad Markush definitions for substituents and ring/heteroatom options, and the scope includes salts, stereoisomers, prodrugs, metabolites, solvates, and hydrates.
The disclosed compounds are used for treating or suppressing mitochondrial disorders by contacting mitochondria in a cell of a subject with a therapeutically effective amount or effective amount of one or more compounds selected from the disclosed Formula I definitions, including salts and stereoisomer mixtures. The method concept is linked to modulation of energy biomarkers associated with mitochondrial function, including lactate/pyruvate and ratios, NADH/NADPH and NAD/NADP, ATP, CoQred/CoQox/CoQtot, cytochrome C redox species, VO2/VCO2 and respiratory quotient (VCO2/VO2), and reactive oxygen species.
The mitochondrial disorders covered include Friedreich's ataxia (FA/FRDA), Leber's Hereditary Optic Neuropathy (LHON), Kearns-Sayre Syndrome (KSS), MELAS, mitochondrial myopathy/encephalopathy/lactacidosis/stroke, CoQ10 deficiency, Parkinson's disease, and Huntington's Disease. The disclosure also describes clinical assessment framework for biomarker efficacy and research/assay use in patient-derived fibroblasts associated with FRDA, Huntington’s, LHON, Parkinson’s, CoQ10-deficient (CoQ2 mutation), and ASD.
Claims Coverage
The consolidated claim coverage identifies one independent claim. The claim centers on treating mitochondrial disorders by contacting mitochondria in a subject cell with therapeutically effective amount(s) of compounds defined by Formula I, including salts, stereoisomers, and stereoisomer mixtures, with the target disorder limited to a defined set.
Contacting mitochondria with Formula I compounds for treating mitochondrial disorders
A method of treating a mitochondrial disorder by contacting mitochondria in a cell of a subject with a therapeutically effective amount or effective amount of one or more compounds selected from Formula I, including salts, stereoisomers, and a mixture of stereoisomers, where the compound substituents are defined by the stated Markush groups.
Mitochondrial disorder selected from a defined set
The mitochondrial disorder is selected from the group consisting of Friedreich's Ataxia (FA), Leber's Hereditary Optic Neuropathy (LHON), Kearns-Sayre Syndrome (KSS), Parkinson's disease, and Huntington's Disease.
Formula I family and subclasses
The disclosure also refers to Formula I compounds, including Formula Ia/Iaa and Formula Ib/Ibb, and the broader Formula I family with defined structural substituent ranges.
The independent claim combines treatment by contacting mitochondria with Formula I compounds and a defined set of mitochondrial disorders. The broader disclosure also refers to Formula subclasses, salts, stereoisomers, and stereoisomer mixtures.
Stated Advantages
Protective activity is reported in patient-derived fibroblasts under the stated stressed conditions.
Treating or suppressing mitochondrial disorders.
Modulating energy biomarkers associated with mitochondrial function.
EC50 values are reported for certain compounds, including values below 100 nM, ASD activity below 300 nM, and one example at 50 nM.
Documented Applications
Use for treating or suppressing mitochondrial disorders including FA/FRDA, LHON, KSS, MELAS, mitochondrial myopathy/encephalencephalopathy/lactacidosis/stroke, CoQ10 deficiency, Parkinson's disease, and Huntington's Disease.
Modulating energy biomarkers such as lactate/pyruvate and ratios, NADH/NADPH and NAD/NADP, ATP, CoQred/CoQox/CoQtot, cytochrome C redox species, VO2/VCO2 and respiratory quotient (VCO2/VO2), and reactive oxygen species.
Research/assay use, including biological screening in patient-derived fibroblasts associated with FRDA, Huntington’s, LHON, Parkinson’s, CoQ10-deficient (CoQ2 mutation), and ASD, with reported protective activity and EC50 values.
Clinical assessment framework for biomarker efficacy.
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