Compositions and methods for the prevention and/or treatment of mitochondrial disease, including Friedreich's ataxia
Inventors
Keefe, Dennis • Zheng, Guozhu • Arsenjans, Pavels
Assignees
Latvijas Organiskās Sintēzes Institūts • Stealth Biotherapeutics Inc
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11584728-B2
Publication Date
2023-02-21
Expiration Date
Abstract
The disclosure provides therapeutic compositions (i.e., therapeutic agents) and methods of preventing or treating Friedreich's ataxia in a mammalian subject, reducing risk factors, signs and/or symptoms associated with Friedreich's ataxia (e.g., Complex I deficiency), and/or reducing the likelihood or severity of Friedreich's ataxia. The disclosure further provides novel intermediates for the production of said therapeutic compositions and related reduced versions of said therapeutic compositions, which reduce forms may also be used as therapeutic agents (or prodrugs of the therapeutic agent(s)).
Core Innovation
The disclosure concerns fluorinated compounds of formula E-F, including pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and/or solvates thereof. E is 21 or 22 and F is 13 or 14, with J, K, L, W, X, Y, Z, R1 through R21, and n defined by structural selection and bonding rules. At least one of the selected R groups comprises at least one fluorine atom, and R8 and R9 taken together form a 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring.
Within the scaffold, J is O, S or N-R11; K is absent or -(CR12R13)-; and L is -(CR12R13)-. Each W is independently C or N, with single-bond or double-bond options and associated hydrogen and substituent rules, and the structure further includes constraints on X, Y, Z, R1-R3, R4-R7, R8-R9, R11, R12-R14, R20, and R21. The compounds also include substituted quinone or hydroquinone head groups and related reduced and oxidized forms.
The disclosure further describes therapeutic use in mitochondrial disease, especially Friedreich’s ataxia, and links the condition to frataxin deficiency, mitochondrial iron overload, Complex I deficiency, oxidative stress, ROS, Fe-S cluster assembly, glutathione depletion, lipid peroxidation, and ferroptosis. The compounds and related forms, including potential therapeutic prodrugs and reduced/oxidized redox pairs, are administered to treat or prevent disease.
Claims Coverage
The consolidated claim coverage centers on one independent claim directed to a fluorinated compound class defined by formula E-F with extensive structural constraints, plus a composition or medicament claim. The inventive features combine the defined scaffold, linker and bonding rules, substituent limitations, fluorine placement requirements, and ring-forming options.
Fluorinated E-F compound scaffold
A compound of formula E-F, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and/or solvates thereof, wherein E is 21 or 22 and F is 13 or 14, with the scaffold defined by J, K, L, W, X, Y, Z, R1-R21, and n.
Linker and bond definition via J, K, L, and W
J is O, S or N-R11; K is absent or -(CR12R13)-; L is -(CR12R13)-; each W is independently C or N; and each W-W linkage follows the stated single-bond or double-bond rules with associated hydrogen and substituent constraints.
Substituent constraints for X, Y, Z, and R1-R3
Each X is independently -(CR12R13)-; each Y is independently absent or -(CR12R13)-; each Z is independently -(CR14)-; and each of R1, R2 and R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl, or C1-C6 alkoxy, with an option for R1 and R2 to together form a specified ring system.
Fluorine-containing and ring-forming tail constraints
At least one group among R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, R14, R20, or R21 comprises at least one fluorine atom, and R8 and R9 taken together form a 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring.
Additional variable constraints and composition or medicament claim
R11, R12-R14, R20, R21, and n are further constrained as stated in the claim family, and a composition or medicament comprising the compound of claim 1 is also provided.
The claim coverage is directed to a fluorinated E-F compound scaffold with detailed variable and bonding constraints, explicit fluorine-containing requirements, and ring-forming limitations for R1/R2 and R8/R9. Dependent coverage further narrows the scaffold and includes a composition or medicament containing the compound.
Stated Advantages
Treating or preventing Friedreich’s ataxia.
Reducing mitochondrial iron and frataxin reduction.
Addressing Complex I deficiency.
Reducing lipoxygenase-15 activity.
Inhibiting ferroptosis.
Reducing frataxin reduction while increasing and/or maintaining frataxin levels.
Modulating intracellular ATP levels.
Compounds E/H/L/M/N show Complex I by-pass activity and protect from BSO and RSL3-induced ferroptosis.
Compounds E/H/L/M/N are stated as not activating Nrf-2.
Compounds E/H/L/M/N meet combined criteria of Complex I by-pass plus protection in both ferroptosis assays and may have broader therapeutic activity.
Documented Applications
Therapeutic use in Friedreich’s ataxia and mitochondrial disease.
Treatment or prevention of disease using the compounds and related reduced or oxidized redox pairs.
Use in relation to frataxin deficiency, Complex I deficiency, mitochondrial iron overload, oxidative stress, ROS, Fe-S cluster assembly, glutathione depletion, lipid peroxidation, and ferroptosis.
A method of treating or preventing Friedreich’s ataxia using the claimed compound.
Use of the claimed compound for reducing mitochondrial iron and frataxin reduction, addressing Complex I deficiency, reducing lipoxygenase-15 activity, inhibiting ferroptosis, and modulating intracellular ATP levels and frataxin levels as described.
A composition or medicament comprising the compound of claim 1.
Treatment of mitochondrial diseases including Friedreich’s ataxia and ataxia with vitamin E deficiency (AVED).
Using assay results to evaluate Complex I by-pass activity in a Rotenone/Oxygraph LO-15/ATP assay and protection from BSO- and RSL3-induced ferroptosis, together with assessment of Nrf-2 activation using an Nrf-2 assay.
Interested in licensing this patent?