Mitochondria-targeted isoketal/isolevuglandin scavengers and uses thereof
Inventors
Dikalov, Sergey I • Amarnath, Venkataraman
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Publication Number
US-12564580-B2
Publication Date
2026-03-03
Expiration Date
Abstract
The use of novel 2-hydroxybenzylamine derivatives as scavengers of isolevuglandins.
Core Innovation
The disclosed invention relates to mitochondria-targeted 2-hydroxybenzylamine compounds, including isoLG/isoketal scavengers such as mito2HOBA, that react with mitochondrial isolevuglandins (isoLGs). The document describes that isoLGs impair mitochondrial respiration, including Complex I activity, and that mitochondrial targeting supports accumulation of mito2HOBA in mitochondria.
The invention is presented as a strategy to scavenge mitochondrial isoLGs using mito2HOBA, thereby preserving mitochondrial respiratory function. The document further states that mito2HOBA preserves respiratory function and improves outcomes in a lipopolysaccharide (LPS) model of sepsis.
The disclosed approach is also described in connection with hypertension-related mitochondrial damage, including elevated mitochondrial isoLG-protein adducts in hypertensive patients. The document reports that mito2HOBA reduces mitochondrial isoLGs and oxidative stress in angiotensin II/TNFα and angiotensin II models, enhances Sirt3 activity, reduces mitochondrial superoxide, limits mPTP opening, preserves ATP production, and attenuates hypertension.
Claims Coverage
The partial content provides one independent claim and refinement by dependent claims. Across the claim set, the inventive coverage is directed to treating or ameliorating sepsis by administering an effective amount of a compound defined by a specific chemical formula, with stereoisomers, pharmaceutical salts, and an optional counterion.
Sepsis treatment with a formula-defined mitochondria-targeted compound
A method of treating or ameliorating sepsis in a subject by administering an effective amount of a compound of the provided chemical formula, where X is a bond, alkyl, alkoxy, —O—, or —CH2—, each R is independent and chosen from C1 to C12 substituted or unsubstituted alkyl, and A is defined by the provided structure, each R1 is independent and chosen from C1 to C12 substituted or unsubstituted alkyl, together with an optional counterion, stereoisomers, and pharmaceutical salts thereof.
Constrained substituent selections for X and R (C1 to C12 alkyl)
In the method of the formula-defined sepsis treatment, X is selected from the specified substituent options and each R is independently chosen from C1 to C12 substituted or unsubstituted alkyl, including stereoisomers and pharmaceutical salts thereof.
Independent R and R1 selections including acetoxymethyl
In the method of the formula-defined sepsis treatment, each R substituent is independently chosen as a C1 to C12 substituted or unsubstituted alkyl group and each R1 substituent is independently chosen as a C1 to C12 substituted or unsubstituted alkyl group or acetoxymethyl, including stereoisomers and pharmaceutical salts.
R2 selection including a —P—Ph3-associated option
In the method of the formula-defined sepsis treatment, R2 is selected from —P—Ph3 or the indicated alternative heteroaromatic cation, including stereoisomers and pharmaceutical salts thereof.
Formula implementation with specified X, R, and R1 options plus stereoisomers and salts
The method comprises administration of a compound having the provided chemical formula in which X and R and R1 are defined with specified substituent and stereoisomer and pharmaceutical salt options.
Administration of pharmaceutically acceptable salts of the formula-defined compound
The method involves compounds of the provided chemical formula, including pharmaceutically acceptable salts thereof.
The claim set focuses on sepsis treatment by administering an effective amount of a compound defined by a specified chemical formula that includes options for X, independent C1–C12 substituted or unsubstituted alkyl selections for R and R1 (with an additional acetoxymethyl option for R1), optional counterion handling, and coverage of stereoisomers and pharmaceutically acceptable salts, with additional coverage refinement including an R2 option that includes a —P—Ph3-associated selection.
Stated Advantages
Preserves mitochondrial respiratory function.
Improves outcomes in a lipopolysaccharide (LPS) model of sepsis.
Reduces mitochondrial isoLGs.
Reduces oxidative stress and mitochondrial superoxide.
Enhances Sirt3 activity.
Limits mitochondrial permeability transition pore (mPTP) opening.
Preserves ATP production.
Attenuates hypertension.
Documented Applications
Treating or ameliorating sepsis using a mitochondria-targeted 2-hydroxybenzylamine (mito2HOBA) compound that scavenges mitochondrial isoLGs.
Hypertension-related mitochondrial damage, including reduction of mitochondrial isoLGs and oxidative stress in angiotensin II/TNFα and angiotensin II models.
Measurement-context evidence in hypertensive patients, including elevated mitochondrial isoLG-protein adducts.
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