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-12144788-B2
Publication Date
2024-11-19
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
The invention relates to methods and compounds for treating ocular disorders by administering retinal sequestering compounds containing primary amines. These compounds modulate the visual (retinoid) cycle by transiently sequestering all-trans-retinal in ocular tissue through the formation of a Schiff base, reducing the toxic peak concentrations of all-trans-retinal without significantly impairing the visual cycle necessary for vision.
The problem addressed is the toxicity caused by elevated levels of all-trans-retinal, a metabolite produced during visual processing which can induce retinal toxicity implicated in diseases such as Stargardt macular dystrophy and age-related macular degeneration. The toxicity arises from the reactive aldehyde functionality of retinaldehyde that damages ocular cells. Existing methods that inhibit enzymes like RPE65 cause undesirable side effects such as delayed dark adaptation, prompting the need for compounds that reduce all-trans-retinal toxicity without substantial enzyme inhibition.
Claims Coverage
The patent includes five independent claims focused on compounds of specified chemical formulas. The inventive features center on structural characteristics of these compounds and their therapeutic use.
Compounds of formula (I) with defined substituents
The invention provides compounds of formula (I) wherein n1, R1, R2, and R3 are defined with specific ranges and chemical groups, including primary amine functionality and lipophilic or hydrophobic alkyl or fluoroalkyl groups, excluding acidic or basic functional groups in R1 in certain embodiments.
Compounds of formula (II) with branched or cyclic alkyl or fluoroalkyl groups
Compounds of formula (II) feature n1, R1 as branched and/or cyclic lipophilic or hydrophobic alkyl or fluoroalkyl groups, R2 as H, CH3, or OH, and R3 as various substituted or unsubstituted alkyl and aryl groups, with pharmaceutically acceptable salts.
Specific selections of R3 substituents for compounds of formula (I) and (II)
Claims specify subsets of R3 substituents selected from particular chemical groups and their fluoro derivatives for compounds of formulae (I) and (II).
Therapeutic use of compounds of formula (I) and (II)
Use of these compounds, including pharmaceutically acceptable salts, in methods of treating ocular disorders by administering therapeutically effective amounts of retinal sequestering compounds.
Compounds of formulas (III), (IV), and (V) with specified substituents
Additional independent claims encompass compounds of formulas (III), (IV), and (V) with defined integers for n1 and specific lipophilic or hydrophobic groups for R1, R2, and R3, extending the scope of the retinal sequestering compounds.
The claims collectively cover novel retinal sequestering compounds characterized by specific chemical structures containing primary amines and hydrophobic substituents, and their use in treating ocular disorders linked to all-trans-retinal toxicity, focusing on compounds that modulate retinal toxicity with or without inhibiting key enzymes of the visual cycle.
Stated Advantages
Retinal sequestering compounds reduce toxicity of all-trans-retinal without impairing the normal visual cycle.
Compounds can protect against retinal phototoxicity even without significant inhibition of RPE65, minimizing side effects like night blindness.
The degree of RPE65 inhibition by these compounds can be tuned to balance therapeutic benefit and adverse effects.
Certain compounds demonstrate improved binding affinity and ocular retention, potentially enhancing efficacy.
Documented Applications
Treatment of ocular disorders related to aberrant accumulation of all-trans-retinal including Stargardt macular dystrophy, age-related macular degeneration (dry and wet forms), diabetic retinopathy, retinitis pigmentosa, genetic retinal dystrophies, and retinal disorders associated with light overexposure or A2E accumulation.
Use in preventing retinal degeneration caused by retinal toxicity through modulation of the visual (retinoid) cycle.
Potential combinatorial therapies with other treatments such as photodynamic therapy for macular degeneration.
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