Classifications

• • 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
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • 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
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
• • 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

Definitions

• retinol-related diseases are macular degenerations, macular dystrophies and retinal dystrophies, including dry- form macular degenerations, geographic atrophy, and/or photoreceptor degeneration.
• methods, compounds, and compositions for the treatment of hyperretinolemia excess serum retinol levels
• methods, compounds and compositions for lowering levels of serum retinol, a serum RBP (retinol binding protein), and/or a serum TTR (transthyretin) in a human subject or patient are also presented herein.
• vitreoretinal diseases such that the level of serum retinol in the body of a patient is lowered.
• the vitreoretinal diseases are macular degenerations, macular dystrophies and retinal dystrophies.
• the vitreoretinal diseases are dry form macular degeneration, photoreceptor degeneration, geographic atrophy, macular dystrophies, diabetic retinopathy, wet form of macular degeneration, retinopathy of prematurity, and/or retinitis pigmentosa.
• a pharmaceutical composition comprising a compound of Formula (I):
• a method of treating a vitreoretinal disease comprising administering to a mammal a therapeutically effective amount of a compound of Formula (I) or (II) wherein the retinol binding protein is RBP4.
• a method of treating a vitreoretinal disease comprising administering to a mammal a therapeutically effective amount of a compound of Formula (I) or (II) wherein the vitreoretinal disease is dry form macular degeneration, photoreceptor degeneration, geographic atrophy, macular dystrophies, diabetic retinopathy, wet form of macular degeneration, retinopathy of prematurity, and retinitis pigmentosa.
• D is isopropyl, isobutyl, sec -butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;
• R is H, an optionally substituted aryl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl; or an active metabolite, or a pharmaceutically acceptable prodrug or solvate thereof.
• the therapeutically effective amount of a compound of Formula (II) is provided in the form of an oral pharmaeutical composition for systemic administration of the compound.
• a method for treating hyperretinolemia comprising administering to a mammal a compound of Formula (I) or (II) wherein hyperretinolemia is associated with a vitreoretinal disease.
• B is a bond ,-(C 2 -C 7 )alkyl, -(C 2 -C 7 )alkenyl, -(C 3 -C 8 )cycloalkyl, -(C 2 -C 7 )heteroalkyl, - (C 3 -C 8 )heterocycloalkyl, -(C 3 -C 8 )cycloalkenyl, -(C 3 -C 8 )heterocycloalkenyl;
• R is H, an optionally substituted aryl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;
• A is O, NH, or S
• D is isopropyl, isobutyl, sec -butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl;
• Figure 10 Effect of test compound on reducing total fluorophore levels in ABCA4-/- mice. Mice were treated as described in Figure 1 (above). At the end of the study, one eye from each animal was used to measure total fluorophore levels. Briefly, one whole eye was homogenized in 1 ml phosphate buffer saline (50 mM Na 2 HPOz I , 150 mM NaCl, pH 7.8). Following homogenization, 1 ml methanol was added and the samples were mixed thoroughly. The mixtures were incubated at room temperature for 5 min and extracted twice with 2 ml hexane. The extracts were concentrated to ⁇ 400 ⁇ l for fluorescence measurements.
• phosphate buffer saline 50 mM Na 2 HPOz I , 150 mM NaCl, pH 7.8
• 1 ml methanol was added and the samples were mixed thoroughly. The mixtures were incubated at room temperature for 5 min and extracted twice with 2 ml hexane.
• A is O, NH, or S;
• B is a bond, -(C 2 -C 7 )alkyl, -(C 2 -C 7 )alkenyl, -(C 3 -C 8 )cycloalkyl, -(C 2 -C 7 )heteroalkyl,
• compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments.
• the term "treating" is used to refer to either prophylactic and/or therapeutic treatments.
• the compositions are administered to a patient already suffering from a disease, condition or disorder, in an amount sufficient to cure or at least partially arrest the symptoms of the disease, disorder or condition. Amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
• compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.
• the administration of the compounds is given continuously or temporarily suspended for a certain length of time (i.e., a "drug holiday").
• a maintenance dose is administered if necessary.
• the dosage or the frequency of administration, or both are reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained.
• patients require intermittent treatment on a long-term basis upon any recurrence of symptoms.
• Purified TTR polypeptides comprising a glutathione-S-transferase protein and adsorbed onto glutathione-derivatized wells of 96-well microtiter plates are contacted with test compounds from a small molecule library at pH 7.0 in a physiological buffer solution.
• Purified TTR polypeptides have been described in the art. See U.S. Patent App. No. 20020160394, herein incorporated by reference.
• the test compounds in some embodiments, comprise a fluorescent tag. The samples are incubated for 5 minutes to one hour. Control samples are incubated in the absence of a test compound.
• the buffer solution containing the test compounds is washed from the wells.
• ETDRS (LogMAR) chart and a standardized refraction and visual acuity protocol. Evaluation of the mean ETDRS (LogMAR) best corrected visual acuity (BCVA) from baseline through the available post-treatment interval visits aids in determining statistical visual improvement. [00352] To assess the ANOVA (analysis of variance between groups) between the control and experimental group, the mean changes in ETDRS (LogMAR) visual acuity from baseline through the available post-treatment interval visits are compared using two-group ANOVA with repeated measures analysis with unstructured covariance using SAS/STAT Software (SAS Institutes Inc, Cary, North Carolina).
• the serum retinol levels are assessed as follows: after acetonitrile precipitation of serum proteins, the concentrations of retinol are determined from the soluble phase by LC/MS. Alternatively, the serum retinol levels are assessed as described in Driskell et al., J Chromatogr, 1982, 231, 439-444 or Futterman et al., Invest. Ophthalmol Vis Sd, 1975, 14, 125. [00354] Toxicity evaluation after the commencement of the study includes check ups every three months during the subsequent year, every four months the year after and subsequently every six months. Plasma levels of the test compound and its metabolite, serum retinol and/or RBP are also assessed during these visits. The toxicity evaluation includes patients using a compound of Formula (I) or (II) as well as the patients in the control group.
• Example 25 Activity of non-retinoid modulators on RBP-TTR and CYP 450
• Example 30c Sublingual (Hard Lozenge) Composition

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• Health & Medical Sciences (AREA)
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• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Epidemiology (AREA)
• Pain & Pain Management (AREA)
• Ophthalmology & Optometry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Emergency Medicine (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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Cited By (11)

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• 2008
  • 2008-09-16 AU AU2008305303A patent/AU2008305303A1/en not_active Abandoned
  • 2008-09-16 WO PCT/US2008/076499 patent/WO2009042444A2/en not_active Ceased
  • 2008-09-16 CA CA2699773A patent/CA2699773A1/en not_active Abandoned
  • 2008-09-16 KR KR1020107009129A patent/KR20100097098A/ko not_active Withdrawn
  • 2008-09-16 EP EP08834564A patent/EP2205234A4/en not_active Withdrawn
  • 2008-09-16 CN CN200880107835A patent/CN101873852A/zh active Pending
  • 2008-09-16 JP JP2010527024A patent/JP2010540541A/ja active Pending
• 2010
  • 2010-03-25 IL IL204728A patent/IL204728A0/en unknown

Non-Patent Citations (1)

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