Visual cycle modulators
Inventors
Palczewski, Krzysztof • Kiser, Philip • Zhang, Jianye • Badiee, Mohsen • Tochtrop, Gregory
Assignees
Case Western Reserve University • US Department of Veterans Affairs
Publication Number
US-11253489-B2
Publication Date
2022-02-22
Expiration Date
2038-02-27
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Abstract
A method of treating an ocular disorder in a subject in need thereof includes administering to the subject a therapeutically effective amount of a retinal sequestering compound of formula (I).
Core Innovation
Visual function in vertebrates depends critically on retinaldehyde, a vitamin A-derived molecule that exists in the 11-cis configuration coupled to rod and cone opsins. Light absorption by 11-cis-retinaldehyde isomerizes it to the all-trans form, leading to activation of phototransduction and visual centers in the brain. Regeneration of the visual pigments requires conversion of all-trans-retinaldehyde back to the 11-cis form via the visual cycle involving enzymes and binding proteins localized in retinal pigment epithelium (RPE) and photoreceptors.
Toxicity arises from retinaldehyde's reactive aldehyde group, which can react with cellular nucleophiles, causing apoptosis and retinal degeneration as observed in diseases such as Stargardt macular dystrophy and age-related macular degeneration (AMD). Deficiencies in proteins like ABCA4 and RDH8 impair retinaldehyde clearance leading to lipofuscin accumulation, containing toxic retinaldehyde-phosphatidylethanolamine adducts.
The invention relates to retinal sequestering compounds containing primary amines that modulate all-trans-retinal accumulation in ocular tissue to reduce toxicity. These compounds form reversible Schiff-base conjugates with all-trans-retinal, transiently sequestering it without substantially impairing the normal retinoid cycle. Compounds including those of formulae (I) to (V) with defined substituents provide therapeutic retinal sequestering agents for treatment of ocular diseases related to aberrant all-trans-retinal accumulation.
Furthermore, certain retinal sequestering compounds selectively inhibit or do not inhibit enzymes like RPE65 involved in retinoid metabolism, thereby avoiding undesirable side effects such as delayed dark adaptation. The invention also discloses methods for selecting effective retinal sequestering compounds through in vitro and in vivo assays measuring retinoid isomerase activity, visual chromophore regeneration, ERG responses, and protection against light-induced retinal degeneration.
Claims Coverage
The claims cover one independent method claim focusing on administration of a specific retinal sequestering compound with defined structural features and functional properties. The coverage encompasses the chemical characteristics of the compound and its biological action in sequestering all-trans-retinal in ocular tissue.
Administration of retinal sequestering compound of formula (II)
A method of decreasing all-trans-retinal accumulation in ocular tissue by administering a therapeutically effective amount of a retinal sequestering compound of formula (II) with specified substituents.
Exclusion of acidic or basic groups in R1 substituent
R1 substituent of the retinal sequestering compound excludes acidic or basic functional groups to ensure desired lipophilicity and activity.
R1 as branched or cyclic C3-C24 alkyl or fluoroalkyl
The R1 substituent is selected as a branched or cyclic alkyl or fluoroalkyl group containing from 3 to 24 carbon atoms enhancing compound properties.
Selection of R3 substituents
The R3 substituent is selected from specified groups, including alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, or alkaryl groups, impacting compound behavior.
Transient sequestration of all-trans-retinal by reversible Schiff base formation
The retinal sequestering compound transiently sequesters all-trans-retinal by forming a reversible Schiff base in ocular tissue without adversely affecting normal retinoid cycle performance.
The claims principally cover a method of treatment using a retinal sequestering compound of formula (II) characterized by specific structural constraints and functional activity in sequestering all-trans-retinal reversibly in ocular tissue, thereby mitigating toxicity without impairing normal visual cycle functions.
Stated Advantages
Retinal sequestering compounds effectively lower toxic all-trans-retinal levels in ocular tissue, reducing retinal degeneration.
Certain compounds avoid inhibiting RPE65 enzymatic activity, thus preventing delayed dark adaptation and night blindness.
The reversible Schiff base formation allows transient sequestration of all-trans-retinal, maintaining visual chromophore regeneration.
Compounds display varied binding affinity and functional activity, allowing tuning to maximize therapeutic benefit and minimize side effects.
Ocular distribution and persistence of compounds permit effective protection against light-induced retinal damage.
Documented Applications
Treatment of ocular disorders related to aberrant accumulation of all-trans-retinal including retinal degeneration, macular degeneration (dry and wet AMD), Stargardt disease, fundus flavimaculatus, retinitis pigmentosa, diabetic retinopathy, Leber's congenital amaurosis, retinal detachment, inflammatory and hereditary retinal diseases, glaucoma, and others explicitly listed.
Protection against light-induced retinal phototoxicity and retinal degeneration in models such as Abca4−/−Rdh8−/− mice.
Use in combination with other therapies, including photodynamic therapy, for conditions like AMD.
Administration for prophylactic and therapeutic treatment in subjects diagnosed with or at risk for retinal diseases involving elevated all-trans-retinal levels.
Formulation in pharmaceutical compositions suitable for ophthalmic, topical, parenteral, oral, and other routes for treatment of visual cycle-related disorders.
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