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WO2025171323A1 - Compositions et méthodes de traitement d'affections oculaires - Google Patents

Compositions et méthodes de traitement d'affections oculaires

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Publication number
WO2025171323A1
WO2025171323A1 PCT/US2025/015101 US2025015101W WO2025171323A1 WO 2025171323 A1 WO2025171323 A1 WO 2025171323A1 US 2025015101 W US2025015101 W US 2025015101W WO 2025171323 A1 WO2025171323 A1 WO 2025171323A1
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WO
WIPO (PCT)
Prior art keywords
amino
retinal
subject
aldehyde
adductor
Prior art date
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Pending
Application number
PCT/US2025/015101
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English (en)
Inventor
Raymond Stevens
Dale BENNYHOFF
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Ren Bioscience LLC
Original Assignee
Ren Bioscience LLC
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Publication date
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Publication of WO2025171323A1 publication Critical patent/WO2025171323A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]

Definitions

  • Oxidative stress plays an important role in diseases of the eye. Those diseases include age- related macular degeneration, glaucoma, cataracts, diabetic retinopathy, degeneration of the retina, uveitis, and dry eye. By accelerating and increasing lipid peroxidation in the cell membrane, for example, oxidative stress results in the formation of aldehydes that are particularly toxic.
  • aldehyde 4-hydroxy-2-nonenal (4-HNE)
  • 4-HNE 4-hydroxy-2-nonenal
  • a method for treating an ophthalmic disease in a subject including administering to a subject in need thereof an aliphatic aldehyde adductor.
  • the aliphatic aldehyde adductor includes any one of the compounds of Formulas I-VII as set forth herein.
  • the aldehyde adductor is set forth as either Formula VI or Formula VII.
  • the ophthalmic disease that is treated includes glaucoma, macular degeneration, diabetic retinopathy, hereditary retinal degeneration, age-related macular degeneration (AMD), non-exudative age-related macular degeneration, exudative (wet) AMD, macular edema, ocular rosacea, amblyopia, cataracts, dry eye, ulceris, photoreceptor degeneration, retinitis pigmentosa, Stargardt disease, Leber Congenital Amaurosis, keratoconus, retrobulbar optic neuritis, loss of conjunctival cells, loss of lacrimal gland cells, central or branch retinal artery occlusions, ocular hypertension, or ocular inflammation.
  • the ophthalmic disease can also be a neurodegenerative disorder of the retina and optic nerve head, uveitis, or a neurodegenerative disorder.
  • the neurodegenerative disorder includes atrophic macular degeneration, retinitis pigmentosa, iatrogenic retinopathy, retinal tears or holes, diabetic retinopathy, sickle cell retinopathy, retinal vein or artery occlusion, or optic neuropathy.
  • the aldehyde adductor targets a reactive aldehyde species.
  • Examples of such reactive aldehyde species that can be targeted include 4-hydroxynonenal (4HNE), 4-hydroxy-2E-hexenal (4-HHE), 2-hydroperoxyeicosa-tetraenoic acid (12-HpETE), 12- hydroxyeicostetrae-noic acid (12-HETE), and 4-hydroxy-2E,6Z-dodecadienal (4-HDDE), malondialdehyde (MDA), acrolein, retinaldehydes, 11-cis retinal, all trans retinal, all trans retinal dimers, all trans retinyl esters, retinol (vitamin A1), or a combinations thereof.
  • a method for targeting a reactive aldehyde species in a subject including administering to the subject one or more of the aliphatic aldehyde adductors set forth in Formulas I-VII, such as the compound of Formula VI or Formula VII.
  • FIG.1 is a graph showing ARPE-19 retinal pigment epithelial cell viability with increasing dosages of REN-101, in an unbuffered solution. Based on these data, an LC50 of 52.9 was determined.
  • FIG.2 is a graph showing ARPE-19 retinal pigment epithelial cell viability with increasing dosages of REN-101, in the presence of buffer. Notably, high concentrations of buffered REN- 101 did significantly impact cell viability.
  • One-way ANOVA Comparison to untreated control.
  • FIG. 3 is a graph showing cell viability in ARPE-19 retinal pigment epithelial cells following treatment with either 12.2 ⁇ M 4HNE alone or with 12.2 ⁇ M 4HNE and either 10 mM glutathione (positive control), 0.5 to 2 mM ascorbic acid (AA) (positive control), or REN-101 at concentrations ranging from 10 mM to 10 -6 mM. As shown, treatment at each REN-101 concentration provided significantly improved percent cell viability (similar to control) verses insult with 12.2 ⁇ m 4-HNE alone.
  • FIG. 4 is a graph showing cell viability in ARPE-19 retinal pigment epithelial cells following treatment with either 200 ⁇ m H 2 O 2 alone or with 200 ⁇ M H 2 O 2 and either 10 mM glutathione (positive control), 0.5 to 2 mM ascorbic acid (AA) (positive control), or REN-101 at concentrations ranging from 10 mM to 10 -6 mM. As shown, treatment at each REN-101 concentration provided a significantly improved percent cell viability (similar to control) verses insult with 200 H2O2 ⁇ m alone.
  • FIG. 5 is a graph showing the effect of REN-101 treatment on 4HNE-induced oxidative stress in ARPE19 retinal pigment epithelial cells.
  • ARPE19 cells were subjected to a CellRox+ TM analysis following treatment with 12.2 ⁇ M 4HNE alone or 12.2 ⁇ M 4HNE with 10.0 mM glutathione (positive control), 0.5 mM ascorbic acid (AA) (positive control), or REN-101 at concentrations ranging from 10 mM to 10 -6 mM.
  • FIG. 6 is a graph showing the effect of REN-101 treatment on H 2 O 2 -induced oxidative stress in ARPE19 retinal pigment epithelial cells.
  • ARPE19 cells were subjected to a CellRox+ TM analysis following treatment with either 200 ⁇ M H2O2 alone or with H2O2 and either 10.0 mM glutathione (positive control), 0.5 mM ascorbic acid (AA) (positive control), or REN-101 at concentrations ranging from 10 mM to 10 -6 mM and H 2 O 2 200 ⁇ M insult. As shown, REN-101 attenuates H 2 O 2 -induced oxidative stress.
  • FIG.7 is a graph showing the effect of REN-101 treatment on H2O2-induced mitochondrial superoxide production in ARPE19 retinal pigment epithelial cells.
  • ARPE19 cells were subjected to a MitoSOX TM analysis following treatment with 200 ⁇ M H2O2 and 10.0 mM glutathione (positive control), or REN-101 at concentrations ranging from 10 mM to 10 -6 mM and H 2 O 2 200 ⁇ M insult.
  • REN-101 attenuates H2O2-induced mitochondrial superoxide production.
  • FIG. 8 is a graph showing the preservational effect of REN-101 treatment on neuroretinal cells (rods, cones, horizontal, bipolar, amacrine and retinal ganglion cells) in the rd10 mouse model.
  • the 500 mg/kg, Ren-101 treated, rd10 mice displayed significantly reduced deterioration of the cells making up the inner and outer retina.
  • the 500 mg/kg dose exhibited a p-value of ⁇ 0.01 at 2.0 mm from the fovea and ⁇ 0.05 at 1.5mm from the fovea versus vehicle.
  • Ren-101 at 1000 mg/kg did not show significance, there too shows consistent improvement in neuroretinal structures over the untreated rd10 mice.
  • FIG.9 is a graph showing the preservational effect of REN-101 treatment on rod and cone cells in the rd10 mouse model.
  • the 500 and 1000 mg/kg Ren- 101 treated rd10 mice exhibited significantly reduced deterioration of rods and cones versus untreated rd10 animals.
  • the 1000 mg/kg Ren-101 treated rd10 animals had a p-value of ⁇ 0.05 at 1.5 mm and 2.0 mm from the fovea, versus vehicle.
  • the 500mg/kg Ren-101 treated mice exhibited a p-value of 0.01 versus vehicle at all four positions from the fovea.
  • FIG.10 is a graph showing the preservational effect of REN-101 treatment on visual acuity on ABCA4 mice following treatment for 24 weeks.
  • mice were treated daily with vehicle, Ren-101 30 mg/kg, Ren-101 100 mg/kg or metformin (active comparator) 500 mg/kg.
  • the visual acuity measure of Optokinetic Tracking Response (OKT) analysis was performed at 9, 13, 17 and 24 weeks. On average, mice consistently maintained their visual function at 24 weeks with no decline from the 9-week baseline, demonstrating sustained effectiveness in preserving sight.
  • ABCA4 mice treated with only vehicle had ⁇ 20% reduction in visual function when comparing 24 weeks to 9 weeks DETAILED DESCRIPTION
  • a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range.
  • description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.
  • administer refers to directly administering a compound (also referred to as an agent of interest) or pharmaceutically acceptable salt of the compound (agent of interest) or a composition to a subject.
  • carrier encompasses carriers, excipients, and diluents, meaning a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in carrying or transporting a pharmaceutical, cosmetic or other agent across a tissue layer such as the stratum corneum or stratum spinosum.
  • disorder is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • the terms “effective amount” and “therapeutically effective amount” are used interchangeably in this disclosure and refer to an amount of a compound that, when administered to a subject, is capable of reducing a symptom of a disorder in a subject or enhance the texture, appearance, color, sensation, or hydration of the intended tissue treatment area.
  • the actual amount which comprises the “effective amount” or “therapeutically effective amount” will vary depending on a number of conditions including, but not limited to, the severity of the disorder, the size and health of the patient, and the route of administration. A skilled medical practitioner can readily determine the appropriate amount using methods known in the medical arts.
  • pharmaceutically acceptable or “cosmetically acceptable” is employed herein to refer to those agents of interest/compounds, salts, compositions, dosage forms, etc., which are- -within the scope of sound medical judgment--suitable for use in contact with the tissues of human beings and/or other mammals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable means approved by a regulatory agency of the federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals (e.g. animals), and more particularly, in humans.
  • salts as used herein embraces pharmaceutically acceptable salts commonly used to form alkali metal salts of free acids and to form additional salts of free bases.
  • the nature of the salt is not critical, provided that it is pharmaceutically acceptable.
  • salts also includes solvates of addition salts, such as hydrates, as well as polymorphs of addition salts.
  • Suitable pharmaceutically acceptable acid addition salts can be prepared from an inorganic acid or from an organic acid.
  • inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid.
  • Appropriate organic acids can be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, and heterocyclyl containing carboxylic acids and sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, 3-hydroxybutyric, galactaric and galactu
  • patient and subject are interchangeable and may be taken to mean any living organism which may be treated with compounds of the present invention.
  • the terms “patient” and “subject” may include, but is not limited to, any non-human mammal, primate or human.
  • the “patient” or “subject” is a mammal, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, or humans.
  • the patient or subject is an adult, child or infant.
  • the patient or subject is a human.
  • treating is used herein, for instance, in reference to methods of treating a disorder or a systemic condition, and generally includes the administration of a compound or composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition or enhance the texture, appearance, color, sensation, or hydration of the intended tissue treatment area of the tissue surface in a subject relative to a subject not receiving the compound or composition. This can include reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in a manner to improve or stabilize a subject’s condition.
  • alkenyl employed alone or in combination with other terms, means, unless otherwise stated, a straight chain or branched chain hydrocarbyl having the stated number of carbon atoms, and containing one or more double bonds. Examples include ethenyl (vinyl), propenyl (allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, and 1,4-pentadienyl.
  • a functional group representing an alkenyl is exemplified by —CH2—CH ⁇ CH2—.
  • aryl groups include, for example, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene and biphenyl. Preferred examples of aryl groups include phenyl and naphthyl.
  • aralkyl group refers to an alkyl group substituted with an aryl group.
  • halo or “halogen” by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • a halogen includes fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
  • heteroarylalkyl refers to an alkyl group substituted with a heteroaryl group.
  • heterocycle or “heterocyclyl” or “heterocyclic” by itself or as part of another substituent means, unless otherwise stated, an unsubstituted or substituted, mono- or multi-cyclic heterocyclic ring system which consists of carbon atoms and at least one heteroatom selected from the group consisting of N, O, and S.
  • the heterocycle typically contains from five to ten ring atoms.
  • the heterocyclic system may be attached to another atom, unless otherwise stated, at any heteroatom or carbon atom of the heterocyclic system which affords a structural isomer.
  • heteroaryl or “heteroaromatic” refers to a heterocycle having aromatic character.
  • hydrocarbyl by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e. C1-C6 means one to six carbons). Examples include: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl.
  • unsaturated hydrocarbyl means a hydrocarbyl that contains at least one double or triple bond.
  • perhaloalkoxy means a haloalkoxy group wherein all the hydrogen atoms are replaced by halogen atoms.
  • a preferred perhaloalkoxy is perfluoroalkoxy, particularly —(C1-C6)perfluoroalkoxy; more preferred is —(C1-C3)perfluoroalkoxy; most preferred is —OCF3.
  • pharmaceutically acceptable refers to a formulation of a compound that does not significantly abrogate the biological activity, a pharmacological activity and/or other properties of the compound when the formulated compound is administered to a patient. In certain embodiments, a pharmaceutically acceptable formulation does not cause significant irritation to a patient.
  • substituted means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.
  • substituted refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position.
  • Substituents may include, for example, one of the moieties from the group of halo, oxy, azido, nitro, cyano, alkyl, alkoxy, alkyl-thio, alkyl-thio-alkyl, alkoxyalkyl, alkylamino, trihalomethyl, hydroxyl, mercapto, hydroxy, alkylsilyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, alkenyl, alkynyl, aryl, and amino groups.
  • Substituents comprising carbon chains preferably contain 1-6, more preferably 1-3, most preferably 1-2, carbon atoms.
  • each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
  • a closed or open-ended numerical range is described herein, all numbers, values, amounts, percentages, subranges and fractions within or encompassed by the numerical range are to be considered as being specifically included in and belonging to the original disclosure of this application as if these numbers, values, amounts, percentages, subranges and fractions had been explicitly written out in their entirety.
  • Indirect carbonylation can occur by reactive ⁇ , ⁇ -unsaturated aldehydes, which are products of oxidative modification of polyunsaturated fatty acids (PUFA).
  • Common reactive aldehydes include 4-hydroxyalkenals, such as 4-hydroxynonenal (4HNE) (also known -hydroxy-2E-nonenal or 4-hydroxy-2-nonenal), 4-hydroxy-2E-hexenal (4- HHE), 2-hydroperoxyeicosa-tetraenoic acid (12-HpETE), 12-hydroxyeicostetrae-noic acid (12- HETE), and 4-hydroxy-2E,6Z-dodecadienal (4-HDDE), malondialdehyde (MDA), acrolein, retinaldehydes, for example, 11-cis retinal, and all trans retinal.
  • 4HNE 4-hydroxynonenal
  • 4-HHE 4-hydroxy-2E-hexenal
  • the aliphatic aldehyde adductors of various embodiments include compounds of general Formula I: (I) and [0067]
  • R 1 are — — — C 8 )alkynyl, substituted or unsubstituted -ara(C 1 -C 6 )alkyl, substituted or unsubstituted -(C 1 - C 6 )heteroarylalkyl, where the substituents can be selected from the group consisting of halogen, —CN, —NO2, —NH2, —NH(C1-C6)alkyl, —N[(C1-C6)alkyl)]2, —OH, (C1-C6)haloalkyl, —(C1- C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, —SH, (C 1 -C 6 )thioalkyl, —SONH 2 , —SO 2 NH 2 , —SO—(C)
  • aliphatic aldehyde adductors include, but are not limited to 2-amino- 6-((3-aminopropyl)amino)hexanoic acid, (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid, 2-amino-6-((3-aminopropyl)amino)hexanoic acid dihydrochloride, (S)-2-amino-6-((3- aminopropyl)amino)hexanoic acid dihydrochloride, 2-amino-5-((6-aminohexyl)amino)pentanoic acid, (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid, 2-amino-5-((6- aminohexyl)amino)pentanoic acid trihydrochloride, (S)-2-amino-6-((
  • the aliphatic aldehyde adductor has the following formula (VI) (referred to herein as “REN-101”): [0087]
  • the various aliphatic aldehyde adductors of the invention contain one or more chiral centers. Embodiments include any possible enantiomers, diastereomers, racemates or mixtures thereof of the compounds of the invention. Such compounds may exist in, and may be isolated as, pure enantiomeric or diastereomeric forms or as racemic mixtures.
  • the aliphatic aldehyde adductors may be isolated as an (S) optical isomer with respect to the configuration about the ⁇ -carbon of the contained ⁇ -amino acid functionality.
  • isolated optical isomer refers to a compound that has been isolated or enriched for the (S) enantiomer of the compound, and in some embodiments, the compound may be substantially purified as the (S) enantiomer from the corresponding optical isomer(s) of the same formula.
  • the isolated optical isomer may be at least about 80 wt. % pure, at least 85 wt. % pure, at least 90 wt. % pure, at least 95 wt.
  • the isolated (S) enantiomer is free of the corresponding (R) enantiomer.
  • the various aliphatic aldehyde adductors described above can be isolated from their reaction mixtures and purified by standard techniques such as filtration, liquid-liquid extraction, solid phase extraction, distillation, recrystallization, or chromatography. [0090] The aliphatic aldehyde adductors may be in salt form when appropriately substituted with groups or atoms capable of forming salts. Such groups and atoms are well known to those of ordinary skill in the art.
  • salts embraces addition salts or free bases which are compounds of the invention.
  • pharmaceutically acceptable salt refers to salts which possess toxicity profiles within a range that affords utility in pharmaceutical applications.
  • Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, phosphoric acids, and the like.
  • Appropriate organic acids include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic organic acids, examples of which include formic, acetic, pivalic, propionic, furoic, mucic, isethionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, ste
  • Suitable pharmaceutically acceptable base addition salts of aliphatic aldehyde adductors of the invention include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, tromethamine, meglumine (N-methylglucamine) and procaine.
  • Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts.
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non- aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
  • suspensions e.g., aqueous or non- aqueous liquid suspensions, oil-in-water
  • Such oral dosage forms can be prepared by combining the aliphatic aldehyde adductors in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques.
  • Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
  • excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants.
  • Binders suitable for use in pharmaceutical compositions and dosage forms provided herein include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.
  • fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions provided herein is present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • Disintegrants are used in the compositions provided herein to provide tablets the ability to disintegrate when exposed to an aqueous environment.
  • Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions.
  • a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms provided herein.
  • the amount of disintegrant used varies based upon the type of formulation.
  • the pharmaceutical compositions provided herein comprise from about 0.5 to about 15 weight percent or from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that are suitable for use in pharmaceutical compositions and dosage forms provided herein include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
  • Lubricants that are suitable for use in pharmaceutical compositions and dosage forms provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
  • Additional lubricants include, but are not limited to, a syloid silica gel (AEROSIL200, W.R. Grace Co., Baltimore, Md.), a coagulated aerosol of synthetic silica (Degussa Co. of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide, Cabot Co. of Boston, Mass.), and mixtures thereof.
  • a syloid silica gel AEROSIL200, W.R. Grace Co., Baltimore, Md.
  • a coagulated aerosol of synthetic silica Degussa Co. of Plano, Tex.
  • CAB-O-SIL a pyrogenic silicon dioxide, Cabot Co. of Boston, Mass.
  • lubricants are used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • a solid oral dosage form comprising one or more of the compounds provided herein, or pharmaceutically acceptable salts thereof; and one or more excipients selected from anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.
  • a solid oral dosage form comprising one or more of the compounds provided herein, or pharmaceutically acceptable salts thereof; and anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.
  • the aliphatic aldehyde adductors can be administered by controlled release means or by delivery devices. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference in its entirety.
  • such dosage forms are to be used to provide slow or controlled-release of one or more active ingredients using, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • active ingredients for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • single unit dosage forms suitable for oral administration including, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.
  • All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
  • controlled-release preparations are characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
  • Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release the drug to maintain this level of therapeutic or prophylactic effect over an extended period of time.
  • the oral dosage form may be a liquid formulation containing the aliphatic aldehyde adductor encapsulated within a capsule or a gelatin capsule (“gelcap”).
  • the capsule in such embodiments can be made of a substance that degrades or otherwise dissociates when exposed to conditions present in the gastro-intestinal tract of a mammal.
  • Capsules and gelcaps are well known in drug delivery technology and one of skill could select such a capsule as appropriate for delivery of a particular active agent.
  • the formulation of the invention generally remains intact, especially for hydrophobic formulations, and passes through the GI tract without emulsification or fragmentation.
  • the capsule may include gelatin or synthetic polymers such as hydroxyethyl cellulose and hydroxypropyl methyl cellulose.
  • Gelcaps can be of the hard or soft variety, including, for example, polysaccharide or hypromellose acetate succinate based caps (e.g., Vegicaps brand, available from Catalent).
  • parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
  • suitable vehicles that can be used to provide parenteral dosage forms provided herein include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • Topical and mucosal dosage forms provided herein include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic preparations, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa. (1980 and 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea and Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels.
  • the average diameter of particles of nanonized formulations can be less than about 100 nm, less than about 20 nm, less than about 5 nm, about 0.5 nm to about 500 nm, about 1 nm to about 200 nm, about 2 nm to about 100 nm, about 3 nm to about 50 nm, and the like or any range or individual particle diameter encompassed by these example ranges.
  • the formulations may include a combination of particle sizes, for example, micronized particles, nano-sized particles, colloidal particles.
  • a subject having an oxidative disease or conditions including administering to the subject one or more of the one or more of the aldehyde adductors described herein.
  • diseases or conditions include, for example, those in which reactive aldehydes either disrupt, or are believed to disrupt or adversely impact, cellular processes such apoptosis, cell division, inflammation, mutation, drug transport, cellular integrity, membrane potential, neurodegeneration, cell-cell interactions, immune cell activation, and/or innate immunity.
  • administering an effective amount of an aliphatic aldehyde adductor to a subject includes administering a dosage of about 0.10 mg to about 1,000 mg per kg of body weight of the subject, such as about 0.1 mg, about 1 mg, about 2 mg, about 5 mg , about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg per kg, about 250 mg per kg, about 300 mg per kg, about 350 mg per kg, about 400 mg per kg, about 450 mg per kg, about 500 mg per kg, 550 mg per kg, 600 mg per kg, 650 mg per kg, 700 mg per kg, 750 mg per kg, 800 mg per kg, 850 mg per kg, 900 mg per kg, 950 mg per kg, 1,000 mg per kg of body weight of the subject, or any range or individual value encompassed by these example ranges.
  • the dosage may include one or more dosage forms, for example two 50 mg oral dosage forms may be administered to the subject for a total dosage.
  • Administering can be carried out by any conventional means, including, for example, tablets, caplets, capsules, such as soft elastic gelatin capsules, cachets, troches, lozenges, dispersions, suppositories, powders, aerosols (e.g., nasal sprays or inhalers), gels, liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs, liquid dosage forms suitable for parenteral administration to a patient, eye drops or other ophthalmic preparations suitable for topical administration, and sterile solids (e.g.,
  • the methods may include repeating administering 1, 2, 3, 4, or 5 times per day for 1, 2, 3, 4, 5, 6, or more days, weeks, months, or years.
  • the compositions of various embodiments may be administered at a dosage and for a duration that produces controlled plasma levels of an aliphatic aldehyde adductor over a particular period.
  • the plasma level may be within an appropriate therapeutic range.
  • An appropriate therapeutic range will vary depending on the subject and the specific compound and formulation administered and can range from femtogram/mL to above microgram/mL for a desired period of time. For example, a single dose of a dosage form described above may result in plasma levels of greater than 5 ng/mL for a period of greater than 8 hours.
  • the plasma level achieved using a single dose may be greater than 5 ng/mL for a period of greater than 10 hours, greater than 12 hours, greater than 14 hours, greater than 16 hours, greater than 18 hours, or greater than 20 hours. In yet other embodiments, the plasma level achieved using a single dose may be greater than 5 ng/mL, greater than 10 ng/mL, greater than 15 ng/mL, greater than 20 ng/mL, greater than 30 ng/mL, greater than 40 ng/mL, or greater than 50 ng/mL for a period of 4, 8, 10, 12, 14, 16, 18, 20 or 24 hours.
  • REN-101 Retinal Pigment Epithelial Cell Viability
  • ARPE-19 retinal pigment epithelial cell viability was examined to determine if there is potential cytotoxicity following treatment with REN-101 in addition to determination of the LC 50 of REN-101.
  • REN-101 was formulated in 0.9% NaCl.
  • ARPE-19 cells were cultured according to manufacturer’s guidelines (DMEM/F12 with 10% FBS in a humidified incubator at 37 °C in 5% CO2, supplemented with 100 U mL ⁇ 1 penicillin and 100 ⁇ g mL ⁇ 1 streptomycin).
  • DMEM/F12 with 10% FBS in a humidified incubator at 37 °C in 5% CO2, supplemented with 100 U mL ⁇ 1 penicillin and 100 ⁇ g mL ⁇ 1 streptomycin.
  • T75 flasks cells were propagated and at 90% confluency, were detached using 0.05% (w/v) Trypsin-0.53 mM EDTA, quenched with complete growth media, and centrifuged at 125G for 8 minutes with the supernatant discarded. Cells were then resuspended in complete growth media and sub cultivated at 1:4 ratio in a T75 flask.
  • REN-101 was formulated by creating a stock of 200 mM (2376 ⁇ l) REN-101 and neutralizing the stock to the same pH as the control media using 1M NaOH (500 ⁇ l) creating a new stock concentration of 165.22 mM. Subsequent dilutions of REN-101 (10 -6 to 100 mM) were made from the neutralised stock.
  • ARPE-19 cells were cultured according to manufacturer’s guidelines (DMEM/F12 with 10% FBS in a humidified incubator at 37 °C in 5% CO2, supplemented with 100 U mL ⁇ 1 penicillin and 100 ⁇ g mL ⁇ 1 streptomycin).
  • DMEM/F12 with 10% FBS in a humidified incubator at 37 °C in 5% CO2, supplemented with 100 U mL ⁇ 1 penicillin and 100 ⁇ g mL ⁇ 1 streptomycin.
  • T75 flasks cells were propagated and at 90% confluency, were detached using 0.05% (w/v) Trypsin-0.53 mM EDTA, quenched with complete growth media and centrifuged at 125G for 8 minutes with the supernatant discarded. Cells were then resuspended in complete growth media and sub cultivated at 1:4 ratio in a T75 flask.
  • REN-101 improved levels of oxidative stress vs. non-treated cells at all concentrations from 10 mM to 10 -6 mM.
  • REN-101 concentrations at 10 -1 mM and 10 -4 mM were the most effective at reducing oxidative stress due to 4HNE (FIG. 5).
  • REN-101 improved levels of oxidative stress vs. non-treated cells at all concentrations from 10 mM to 10 -6 mM.
  • REN-101 concentrations at 10 -1 mM and 10 -3 mM were the most effective at reducing oxidative stress due to H2O2 (FIG. 6).
  • mice were anaesthetized with ketamine (Vetoquinol UK Ltd) and Rompun (Bayer Health Care) after pupil dilation with Atropine Sulfate and Phenylephrine Hydrochloride (Minims). Eyes were moisturized and prevented from drying out via application of Viscotears Liquid Gel (Bausch + Lomb). Scotopic ERG were recorded via mouse corneal ERG electrodes in response to a single white light flash produced by the Diagnosys Espion ERG system. For each animal, 8 light intensities ranging from 0.008 to 25 cds/m2 were applied. A-wave and B-wave amplitudes were subsequently measured using the Espion analysis software (Diagnosys Technologies, USA).
  • Ren-101 at doses of 500 mg/kg and 1000 mg/kg surprisingly resulted in preservation of retinal cell structures compared to vehicle treated animals with the 500 mg/kg dose showing superior retinal preservation over the positive control, 500 mg/kg metformin.
  • the marked improvement in retinal preservation of Ren-101 compared to the known compound metformin underscores the efficacy of Ren-101.
  • Example 6 Ren-101, 100 mg/kg, Treated Mice Maintained Visual Function in ABCA4 Mice for 24 Weeks [00173] This example provides results from a study assessing visual function via optokinetic tracking response (OKT) analysis in ABCA4 mice following treatment with Ren-101.
  • OKT optokinetic tracking response
  • the ABCA4 (Abca4 tm1Ght /J) mouse model is widely used to study Stargardt disease and related retinal degenerative conditions. This model was generated by deleting the protein-coding sequence of the Abca4 gene, which encodes a critical transmembrane transporter protein in photoreceptor cells. The absence of functional ABCA4 protein disrupts the clearance of all-trans-retinal from photoreceptor outer segments, leading to the accumulation of toxic bisretinoid compounds such as A2E in the retinal pigment epithelium (RPE). This results in lipofuscin buildup, RPE degeneration, and progressive photoreceptor cell loss, mimicking key pathological features of Stargardt disease.
  • RPE retinal pigment epithelium
  • mice A total of 30 mice (24 x ABCA4 and 6 x 129S1/svlmJ wild type controls) aged 14 days were included in the study. See Table 8 for the study design and dosing regimen. Random allocation of same sexed animals to treatment groups was carried out using GraphPad. Sample size was calculated using power analysis and the study was blinded to the assessor. [00175] Dosing solutions of Ren-101 and Metformin were prepared at 10mg/mL in 0.9% NaCl. Route of administration was via oral gavage.

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Abstract

La présente invention concerne des méthodes de traitement d'une maladie ophtalmique à l'aide de compositions contenant un adduit d'aldéhyde aliphatique.
PCT/US2025/015101 2024-02-09 2025-02-07 Compositions et méthodes de traitement d'affections oculaires Pending WO2025171323A1 (fr)

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US20230172886A1 (en) * 2020-04-24 2023-06-08 Temple University-Of The Commonwealth System Of Higher Education (s)-2-amino-6-((3-aminopropyl)amino)hexanoic acid (apl) for use in the treatment of non-alcoholic steatohepatitis (nash), liver inflammation, hepatocellular ballooning, liver fibrosis and steatosis

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Publication number Priority date Publication date Assignee Title
US20230172886A1 (en) * 2020-04-24 2023-06-08 Temple University-Of The Commonwealth System Of Higher Education (s)-2-amino-6-((3-aminopropyl)amino)hexanoic acid (apl) for use in the treatment of non-alcoholic steatohepatitis (nash), liver inflammation, hepatocellular ballooning, liver fibrosis and steatosis

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DATABASE PUBCHEM COMPOUND 16 September 2004 (2004-09-16), XP093346126, Database accession no. 1123 *
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