Compounds and methods of treating retinal degeneration
Inventors
Palczewski, Krzysztof • Chen, Yuanyuan
Assignees
Case Western Reserve University • University of Pittsburgh
Publication Number
US-12251373-B2
Publication Date
2025-03-18
Expiration Date
2038-04-30
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Abstract
A method of treating retinal degeneration in a subject includes administering to the subject a therapeutically effective amount of a compound of formula (I).
Core Innovation
The invention provides compounds, particularly small molecule chaperones of rhodopsin, and methods for treating retinal degeneration in subjects. These compounds, exemplified by formulas (I), (II), (III), and (IV), are designed to stabilize mutant rhodopsin proteins in photoreceptor cells. By promoting proper folding, glycosylation, and transport of unstable mutant opsins such as P23H from the endoplasmic reticulum to the plasma membrane, the compounds restore rhodopsin homeostasis and inhibit photoreceptor cell death related to retinal degeneration.
Inherited retinal degenerations, including retinitis pigmentosa and associated with mutations like P23H in the RHO gene, lead to misfolded rhodopsin proteins that disrupt photoreceptor function and survival. Despite the clinical significance of these disorders, most currently lack effective and safe treatments. The disclosed invention addresses these unmet needs by providing pharmacological chaperones that act directly on the rhodopsin protein and help preserve rod photoreceptor cells.
The compounds can be administered to subjects in need of treatment for retinal degeneration through various routes, including topical, systemic, intravitreal, and intraocular delivery. The method and compositions are applicable to a range of retinal degenerative diseases, such as macular degeneration (including age-related macular degeneration), Stargardt disease, and retinitis pigmentosa, particularly forms linked to rhodopsin misfolding mutations.
Claims Coverage
The patent includes several independent claims, each defining a central inventive feature related to novel compounds with specific structural formulas and their derivatives for treating retinal degeneration.
Compound having formula (I)
A compound represented by formula (I), which includes specified structural components: - X1 is CH2, C═O, or N—R3. - X2 is O or N—R4. - R1 and R2 are each independently selected from hydrogen, substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, and heteroaryl, with at least one of R1 or R2 not being hydrogen. - R3 and R4 are each independently selected from hydrogen or a substituted or unsubstituted C1–C24 alkyl, C2–C24 alkenyl, C2–C24 alkynyl, C3–C20 aryl, heteroaryl, and various described functional groups. - Includes pharmaceutically acceptable salts thereof.
Compound having formula (III)
A compound represented by formula (III) with the following structure: - R2 and R6 are each individually hydrogen, a substituted or unsubstituted C1–C24 alkyl, C2–C24 alkenyl, C2–C24 alkynyl, C3–C20 aryl, heteroaryl, heterocycloalkenyl (containing 5–6 ring atoms, including specified heteroatoms), C6–C24 alkaryl, C6–C24 aralkyl, halo, —Si(C1–C3 alkyl)3, hydroxyl, sulfhydryl, C1–C24 alkoxy, C2–C24 alkenyloxy, C2–C24 alkynyloxy, C5–C20 aryloxy, acyl, acyloxy, C2–C24 alkoxycarbonyl, C6–C20 aryloxycarbonyl, C2–C24 alkylcarbonato, C6–C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1–C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1–C24 alkyl amino, C5–C20 aryl amino, C2–C24 alkylamido, C6–C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1–C24 alkylsulfanyl, arylsulfanyl, C1–C24 alkylsulfinyl, C5–C20 arylsulfinyl, C1–C24 alkylsulfonyl, C5–C20 arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, or phosphino, or combinations thereof. - Includes pharmaceutically acceptable salts thereof.
Compound having formula (IV)
A compound represented by formula (IV), wherein: - R2 and R7 are each individually hydrogen, a substituted or unsubstituted C1–C24 alkyl, C2–C24 alkenyl, C2–C24 alkynyl, C3–C20 aryl, heteroaryl, heterocycloalkenyl (containing 5–6 ring atoms with allowed heteroatoms), C6–C24 alkaryl, C6–C24 aralkyl, halo, —Si(C1–C3 alkyl)3, hydroxyl, sulfhydryl, C1–C24 alkoxy, C2–C24 alkenyloxy, C2–C24 alkynyloxy, C5–C20 aryloxy, acyl, acyloxy, C2–C24 alkoxycarbonyl, C6–C20 aryloxycarbonyl, C2–C24 alkylcarbonato, C6–C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1–C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1–C24 alkyl amino, C5–C20 aryl amino, C2–C24 alkylamido, C6–C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1–C24 alkylsulfanyl, arylsulfanyl, C1–C24 alkylsulfinyl, C5–C20 arylsulfinyl, C1–C24 alkylsulfonyl, C5–C20 arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, or phosphino, or combinations thereof. - Includes pharmaceutically acceptable salts thereof.
The independent claims focus on specific structurally defined small molecule compounds intended to act as rhodopsin chaperones, covering their chemical variants and pharmaceutically acceptable salts. These inventive features are directed toward the treatment of retinal degeneration associated with inherited rhodopsin mutations.
Stated Advantages
The compounds can stabilize mutant rhodopsin in photoreceptor cells and restore rhodopsin homeostasis.
They can rescue the transport and glycosylation of unstable mutant opsin from the endoplasmic reticulum to the plasma membrane, preventing photoreceptor cell death.
The compounds can be administered by multiple routes, including topical, systemic, intravitreal, or intraocular delivery.
Treatment with the compounds does not affect the visual chromophore regeneration or cause mutagenicity or acute toxicity at tested doses.
They provide a therapeutic strategy for retinal degeneration types that currently lack effective and safe treatments.
The compounds do not inhibit cyclooxygenase-1 activity, indicating no interference with this common enzymatic pathway.
Documented Applications
Method of treating retinal degeneration in a subject by administering a therapeutically effective amount of a small molecule compound acting as a rhodopsin chaperone.
Treatment of retinal degeneration associated with inherited rhodopsin mutations in ocular tissue, including macular degeneration, Stargardt disease, and retinitis pigmentosa.
Specific treatment of autosomal dominant retinitis pigmentosa associated with a P23H RHO mutation.
Protection of photoreceptor cells from bright light-induced damage in animal models by preconditioning with the compound.
Inhibition of early ER-associated protein degradation in photoreceptor cells of the subject.
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