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WO2013166040A1 - S-fta et analogues de s-fta pouvant inhiber l'interaction de rbp4-ttr dépendante du rétinol pour le traitement de la dégénérescence maculaire liée à l'âge, de la maladie de stargardt et d'autres maladies de la rétine caractérisées par une accumulation excessive de lipofuscine - Google Patents

S-fta et analogues de s-fta pouvant inhiber l'interaction de rbp4-ttr dépendante du rétinol pour le traitement de la dégénérescence maculaire liée à l'âge, de la maladie de stargardt et d'autres maladies de la rétine caractérisées par une accumulation excessive de lipofuscine Download PDF

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Publication number
WO2013166040A1
WO2013166040A1 PCT/US2013/038908 US2013038908W WO2013166040A1 WO 2013166040 A1 WO2013166040 A1 WO 2013166040A1 US 2013038908 W US2013038908 W US 2013038908W WO 2013166040 A1 WO2013166040 A1 WO 2013166040A1
Authority
WO
WIPO (PCT)
Prior art keywords
rbp4
fta
retinol
compound
macular degeneration
Prior art date
Application number
PCT/US2013/038908
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English (en)
Inventor
Konstantin Petrukhin
Nicoleta DOBRI
Donald W. Landry
Original Assignee
The Trustees Of Columbia University In The City Of New York
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Trustees Of Columbia University In The City Of New York filed Critical The Trustees Of Columbia University In The City Of New York
Publication of WO2013166040A1 publication Critical patent/WO2013166040A1/fr

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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
    • A61K31/202—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 having three or more double bonds, e.g. linolenic
    • 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
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate

Definitions

  • FIG. 3 Structure of bisretinoid A2-DHP-PE, a cytotoxic component of retinal lipofuscin.
  • RBP4 binding assay Head-to-head comparison of S-FTA and Compound 3 in binding assay; Compound 3 is proven to be an RBP4 ligand that is slightly less active than S-FTA in this assay.
  • the amount of a compound of the invention may be effective to lower the retinal concentration of a bisretinoid in lipofuscin in the mammal.
  • the bisretinoid is A2E. In some embodiments the bisretinoid is isoA2E. In some embodiments the bisretinoid is A2-DHP-PE. In some embodiments the bisretinoid is atRAL di-PE.
  • bisretinoid-mediated macular degeneration may be Age-Related Macular Degeneration or Stargardt Disease.
  • the bisretinoid-mediated macular degeneration is dry (atrophic) Age-Related Macular Degeneration. In some embodiments, the bisretinoid-mediated macular degeneration is Stargardt Disease.
  • the bisretinoid-mediated macular degeneration is Stargardt-like macular dystrophy.
  • the disease characterized by excessive lipofuscin accumulation in the retina is adult vitelliform maculopathy . In some embodiments, the disease characterized by excessive lipofuscin accumulation in the retina is Stargardt-like macular dystrophy.
  • the bisretinoid-mediated macular degeneration may comprise the accumulation of lipofuscin deposits in the retinal pigment epi helium.
  • the present invention also provides a compound having the structure:
  • the ester may have the structure:
  • 0.2-5 mg/kg/day is a disclosure of 0.2 mg/kg/day, 0.3 mg/kg/day, 0.4 mg/kg/day, 0.5 mg/kg/day, 0.6 mg/kg/day etc . up to 5.0 mg/kg/day.
  • bisretinoid lipofuscin is lipofuscin containing a cytotoxic bisretinoid.
  • Cytotoxic bisretinoids include but are not necessarily limited to A2E, isoA2E, atRAL di-PE, and A2-DHP-PE (Fig. 1-3).
  • the compounds and compositions of the present invention are useful for the treatment of lipofuscin-mediated macular degeneration.
  • Compounds of the present invention include those in Table 1. Table 1. Structure of Farnesoids .
  • S-Farnesyl Thioacetic Acid has the structure:
  • S-FTA may be purchased from Cayman Chemical Company as a solution in ethanol (Ann Arbor, Michigan, USA; Catalog No. 63260) .
  • Cayman Chemical Company suggests that S-FTA be stored as supplied at -20°C, and that it should be stable for at least one year.
  • the ethanol may be evaporated under a gentle stream of nitrogen and the solvent of choice immediately added.
  • Solvents such as ethanol, DMSO, and dimethyl formamide purged with an inert gas can be used.
  • the solubility of S-FTA in these solvents is about 20 mg/ml. Further dilutions of the stock solution into aqueous buffers or isotonic saline may be made prior to performing biological experiments.
  • organic solvents may have physiological effects at low concentrations, it should be ensured that the residual amount of organic solvent is insignificant.
  • an organic solvent-free solution of S-FTA can be prepared by evaporating the ethanol and directly dissolving the neat oil in aqueous buffers.
  • S-FTA may be directly dissolved in 0.1 M Na 2 C0 3 (63 mg/ml) and then diluted with PBS (pH 7.2) to achieve the desired concentration or pH.
  • PBS pH 7.2
  • pharmaceutically active is used to characterize a substance, compound, or composition suitable for administration to a subject and furnishes biological activity or other direct effect in the treatment, cure, mitigation, diagnosis, or prevention of disease, or affects the structure or any function of the subject.
  • Pharmaceutically active agents include, but are not limited to, substances and compounds described in the Physicians' Desk Reference ( DR Network, LLC; 64th edition,- November 15, 2009) and "Approved Drug Products with Therapeutic Equivalence Evaluations" (U.S. Department of Health and Human Services, 30 th edition, 2010) , which are hereby incorporated by reference .
  • Ester derivatives of compounds may be generated from a carboxylic acid group in accordance with the present invention using standard esterification reactions and methods readily available and known to those having ordinary skill in the art of chemical synthesis. Ester derivatives may serve as pro- drugs that can be converted into compounds of the invention by serum esterases.
  • the compounds used in the method of the present invention may be prepared by techniques well know in organic synthesis and familiar to a practitioner ordinarily skilled in the art. However, these may not be the only means by which to synthesize or obtain the desired compounds.
  • Nonspecific binding was determined in the presence of 20 ⁇ of unlabeled retinol.
  • the reaction mix was assembled in the dark under dim red light.
  • the plates were sealed with clear tape (TopSeal-A: 96-well microplate, PerkinElmer), wrapped in the aluminum foil, and allowed to equilibrate 6 hours at room temperature followed by overnight incubation at +4°C. Radiocounts were measured using a TopCount NXT counter (Packard Instrument Company) .
  • the retinol - binding site on RBP4 is sterically proximal to the interface mediating the RBP4-TTR interaction.
  • the data herein show that small molecule RBP4 antagonists displacing retinol from RBP4 and disrupting the RBP4-TTR interaction will reduce serum retinol concentration, inhibit retinol uptake into the retina and act as indirect visual cycle inhibitors reducing formation of cytotoxic A2E .
  • RBP4 represents an attractive drug target for indirect pharmacological inhibition of the visual cycle and A2E formation.
  • the retinol-binding site on RBP4 is sterically proximal to the interface mediating the RBP4-TTR interaction.
  • Retinol antagonists competing with serum retinol for binding to RBP4 while blocking the RBP4-TTR interaction would reduce serum RBP4 and retinol levels which would lead to reduced uptake of retinol to the retina.
  • the outcome would be visual cycle inhibition with subsequent reduction in the A2E synthesis .
  • Fenretinide was shown to reduce serum RBP4 and retinol (15) , inhibit ocular all-trans retinol uptake and slow down the visual cycle (11) .
  • fenretinide administration reduced A2E production in an animal model of excessive bisretinoid accumulation, Abca4 -/- mice (11) .
  • Pre-clinical experiments with fenretinide validated RBP4 as a drug target for dry AMD.
  • fenretinide is non-selective and toxic.
  • fenretinide Independent of its activity as an antagonist of retinol binding to BP4, fenretinide is an extremely active inducer of apoptosis in many cell types (16-19), including the retinal pigment epithelium cells (20) . It has been suggested that fenretinide' s adverse effects are mediated by its action as a ligand of a nuclear receptor RAR (21-24) . Additionally, similar to other retinoids, fenretinide is
  • the TR-FRET assay was developed and optimized for compounds antagonizing retinol-dependent RBP4-TTR interaction using purified MBP-tagged RBP4 and apo-TTR directly labeled with Eu3+-cryptate.
  • the assay was used to screen several commercial libraries of compounds with drug-like properties. Positive compounds were further evaluated using the developed competition binding assays which unutilized the scintillation proximity (SPA) format for probing the displacement of tritiated retinol from MBP-RPB4. Medicinal chemistry optimization of one positive compound was attempted in order to establish the SAR, structure-activity relationship, in this structural series.
  • SPA scintillation proximity
  • the present invention provides compounds that will preserve vision in AMD patients , Stargardt disease patients , and patients suffering from conditions characterized by excessive accumulation of lipofuscin.
  • N-(4- hydroxyphenyl) retinamide induces retinol- binding protein secretion from liver and accumulation in the kidneys in rats. J Nutr. 1993 Sep; 123 (9) : 1497-503 Adams WR, Smith JE, Green MH. Effects of N-(4- hydroxyphenyl ) retinamide on vitamin A metabolism in rats. Proc Soc Exp Biol Med. 1995 Feb; 208 (2 ): 178-85.
  • N- (4-hydroxyphenyl) retinamide induces apoptosis in human retinal pigment epithelial cells: retinoic acid receptors regulate apoptosis, reactive oxygen species generation, and the expression of heme oxygenase-1 and Gaddl53. J Cell Physiol. 2006 Dec;209 (3) :854-65
  • Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes . ature . 2005 Jul 21;436(7049) :356-62.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une méthode de traitement d'une maladie caractérisée par une accumulation excessive de lipofuscine dans la rétine chez un mammifère atteint de cette pathologie. La méthode consiste à administrer au mammifère une quantité efficace d'un composé de structure (I), dans laquelle X est O ou S, ou un ester ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/US2013/038908 2012-05-01 2013-04-30 S-fta et analogues de s-fta pouvant inhiber l'interaction de rbp4-ttr dépendante du rétinol pour le traitement de la dégénérescence maculaire liée à l'âge, de la maladie de stargardt et d'autres maladies de la rétine caractérisées par une accumulation excessive de lipofuscine WO2013166040A1 (fr)

Applications Claiming Priority (2)

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US201261641089P 2012-05-01 2012-05-01
US61/641,089 2012-05-01

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WO2013166040A1 true WO2013166040A1 (fr) 2013-11-07

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8980924B2 (en) 2010-11-24 2015-03-17 The Trustees Of Columbia University In The City Of New York Non-retinoid RBP4 antagonist for treatment of age-related macular degeneration and stargardt disease
US9333202B2 (en) 2012-05-01 2016-05-10 The Trustees Of Columbia University In The City Of New York Non-retinoid antagonists for treatment of age-related macular degeneration and stargardt disease
US9434727B2 (en) 2014-04-30 2016-09-06 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US9637450B2 (en) 2013-03-14 2017-05-02 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US9938291B2 (en) 2013-03-14 2018-04-10 The Trustess Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US9944644B2 (en) 2013-03-14 2018-04-17 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US10273243B2 (en) 2013-03-14 2019-04-30 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use

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US5312814A (en) * 1992-12-09 1994-05-17 Bristol-Myers Squibb Co. α-phosphonocarboxylate squalene synthetase inhibitors
US5523430A (en) * 1994-04-14 1996-06-04 Bristol-Myers Squibb Company Protein farnesyl transferase inhibitors
US6372793B1 (en) * 1999-08-20 2002-04-16 Florida Agricultural & Mechanical University Method for treatment of a neurological disease characterized by impaired neuromodulator function
US20080254140A1 (en) * 2004-08-18 2008-10-16 Kenneth Widder Combination Methods and Therapies for Treating Opthalmic Conditions with 13-Cis-Retinyl Derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5312814A (en) * 1992-12-09 1994-05-17 Bristol-Myers Squibb Co. α-phosphonocarboxylate squalene synthetase inhibitors
US5523430A (en) * 1994-04-14 1996-06-04 Bristol-Myers Squibb Company Protein farnesyl transferase inhibitors
US6372793B1 (en) * 1999-08-20 2002-04-16 Florida Agricultural & Mechanical University Method for treatment of a neurological disease characterized by impaired neuromodulator function
US20080254140A1 (en) * 2004-08-18 2008-10-16 Kenneth Widder Combination Methods and Therapies for Treating Opthalmic Conditions with 13-Cis-Retinyl Derivatives

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8980924B2 (en) 2010-11-24 2015-03-17 The Trustees Of Columbia University In The City Of New York Non-retinoid RBP4 antagonist for treatment of age-related macular degeneration and stargardt disease
US9333202B2 (en) 2012-05-01 2016-05-10 The Trustees Of Columbia University In The City Of New York Non-retinoid antagonists for treatment of age-related macular degeneration and stargardt disease
US10570148B2 (en) 2013-03-14 2020-02-25 The Trustees Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US11919913B2 (en) 2013-03-14 2024-03-05 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US9637450B2 (en) 2013-03-14 2017-05-02 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US9926271B2 (en) 2013-03-14 2018-03-27 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US9938291B2 (en) 2013-03-14 2018-04-10 The Trustess Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US9944644B2 (en) 2013-03-14 2018-04-17 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US11028098B2 (en) 2013-03-14 2021-06-08 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US10273243B2 (en) 2013-03-14 2019-04-30 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US10787453B2 (en) 2013-03-14 2020-09-29 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US10421720B2 (en) 2013-03-14 2019-09-24 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US9777010B2 (en) 2014-04-30 2017-10-03 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10407433B2 (en) 2014-04-30 2019-09-10 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10913746B2 (en) 2014-04-30 2021-02-09 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10072016B2 (en) 2014-04-30 2018-09-11 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US11649240B2 (en) 2014-04-30 2023-05-16 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US9434727B2 (en) 2014-04-30 2016-09-06 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use

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