WO2015186144A2 - Procédé d'inhibition de la bêta-sécrétase au moyen de bis-o-déméthylcurcumine pour la prévention, la prise en charge et le traitement de maladies neurodégénératives - Google Patents

Procédé d'inhibition de la bêta-sécrétase au moyen de bis-o-déméthylcurcumine pour la prévention, la prise en charge et le traitement de maladies neurodégénératives Download PDF

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Publication number
WO2015186144A2
WO2015186144A2 PCT/IN2015/000232 IN2015000232W WO2015186144A2 WO 2015186144 A2 WO2015186144 A2 WO 2015186144A2 IN 2015000232 W IN2015000232 W IN 2015000232W WO 2015186144 A2 WO2015186144 A2 WO 2015186144A2
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Prior art keywords
bis
demethylcurcumin
secretase
pharmaceutical compositions
disease
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PCT/IN2015/000232
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English (en)
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WO2015186144A3 (fr
Inventor
Ganga Raju Gokaraju
Rama Raju Gokaraju
Trimurtulu Golakoti
Venkateswarlu Somepalli
Kiran Bhupathiraju
Ramchand Nanappan Chaniyilparampu
Nirvanashetty Somashekara
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Laila Pharmaceuticals Pvt. Ltd.
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Publication of WO2015186144A2 publication Critical patent/WO2015186144A2/fr
Publication of WO2015186144A3 publication Critical patent/WO2015186144A3/fr

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    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/13—Amines
    • 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
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to a novel method of inhibiting the Beta-secretase enzyme by using Bis-O-demethylcurcumin.
  • the present invention further discloses the prevention, management and treatment of Alzheimer's disease (AD) by the inhibition of Beta-secretase using Bis-O-demethylcurcumin.
  • the present invention further discloses the process of synthesizing Bis-O-demethylcurcumin and the compositions comprising the same.
  • AD Alzheimer's disease
  • Alzheimer's disease is characterized by two major pathologic observations in the brain viz., neurofibrillary tangles and beta amyloid plaques leading to neuronal loss.
  • Extracellular beta-amyloid ( ⁇ ) deposits or plaques and intracellular neurofibrillary tangles (NFTs) are known to be fundamental cause of the disease. It is generally accepted that the main constituent of amyloid plaques is the 4 kD amyloid protein ( ⁇ 4, also referred to as ⁇ , ⁇ -protein and ⁇ AP)derived from the amyloid precursor protein (APP).
  • ⁇ which is a crucial step in AD pathogenesis, is the result of cleavage of Amyloid Precursor Protein (APP)[Griffm, 2006], by ⁇ -secretase followed by ⁇ -secretase.
  • APP Amyloid Precursor Protein
  • SP ⁇ senile plaques
  • NFTs Intracellular Neurofibrillary Tangles
  • tau protein is a component of microtubules, which are the internal support structures for the transport of nutrients, vesicles, mitochondria and chromosomes within the cell. Microtubules also stabilize growing axons necessary for the development and growth of neurons [Griffin, 2006].
  • AD Alzheimer's disease
  • tau protein is abnormally hyperphosphorylated and forms insoluble fibrils, causing deposits within the cell.
  • Accumulation of amyloid plaques and Neurofibrillary Tangles in the brain leads- to neuronal cell death, which in turn responsible for symptoms associated with AD.
  • Cholinesterase inhibitors The cholinergic hypothesis of AD concludes that cholinergic systems in the basal forebrain are affected early in the disease process, including loss of acetylcholine neurons, loss of enzymatic function for acetylcholine synthesis and degradation, resulting in memory loss and deterioration of other cognitive and noncognitive functions such as neuropsychiatric symptoms [Bartuset al. 1982; Cummings and Back, 1998].
  • a strategy to enhance the cholinergic transmission by using Cholinesterase inhibitors to delay the degradation of acetylcholine between the synaptic cleft has been proposed.
  • N-methyl-D-aspartate antagonist rMemantine is one of the therapeutic option for moderate to severe AD (Lundbeck, Valby, Denmark). Memantine is an uncompetitive, moderate- affinity N-methyl-D-aspartate (NMD A) antagonist believed to protect neurons from excitotoxicity.
  • NMD A N-methyl-D-aspartate
  • Anti-amyloid aggregation agents The only ⁇ aggregation inhibitor reaching phase III is the synthetic glycosaminoglycan 3-amino- 1-propaneosulfonic acid (3 APS, tramiprosate) [Gauthier et al. 2009]. It is designed to interfere with the binding of glycosaminoglycanes and ⁇ . However, recent data suggest that tramiprosatepromotes an abnormal aggregation of the tau protein in neuronal cells [Santa-Maria et al. 2007]. Another molecule undergoing testing is colostrinin, a proline-rich polypeptide complex derived from sheep colostrum (O-CLN; ReGen Therapeutics, London, UK).
  • Colostrinin inhibits ⁇ aggregation and neurotoxicity in cellular assays and improves cognitive performance in animal models. Although a phase II trial demonstrated modest improvements in Mini Mental State Evaluation scores for patients with mild AD over a treatment period of 15 months, this beneficial effect was not sustained during an additional 15 months of continued treatment [Bilikiewicz and Gaus, 2004].
  • scyllo-inositol is able to stabilize oligomeric aggregates of ⁇ and inhibit ⁇ toxicity in mouse hippocampus.
  • An 18-month, randomized, double- blind, placebo controlled, dose-ranging, safety and efficacy study of oral scyllo-inositol (ELND005) in participants with mild to moderate AD has been carried out by Transition Therapeutics (Toronto, ON, Canada)/Elan (Dublin, Ireland).
  • Transition Therapeutics Toronto, ON, Canada
  • Elan Dublin, Ireland
  • a long-term follow-up class II study in subjects with AD provided insufficient evidence to support or refute a benefit of ELND005.
  • ⁇ is generated through proteolytic processing of the transmembrane protein called as Amyloid Precursor protein (APP).
  • APP can be cleaved by three competing proteases, a-secretase , ⁇ -secretase (BACE1) and ⁇ -secretase. Cleavage by ⁇ -secretase, followed by ⁇ -secretase, will lead to production of ⁇ 40 and ⁇ 42.
  • BACE1 ⁇ -secretase
  • BACE1 -cleavage of APP is the rate- limiting step in producing ⁇ ; therefore, much of the effort has focused on identifying BACE1 inhibitors.
  • ⁇ -secretase (BACE1) is considered as one of the most promising therapeutic targets for blocking ⁇ production.No side effects are foreseen from the inhibition of BACE1.
  • BACE1 ⁇ -secretase
  • ⁇ -secretase inhibitors Few of the recently developed ⁇ -secretaseinhibitors are shown to be potent and selective experimental animals.
  • continuous administration of a ⁇ -secretase inhibitor was shown to rescue age-related cognitive decline in transgenic AD mice. A few ⁇ -secretase inhibitors have also entered early phase clinical trials.
  • Figurel Transportation of Formulated LI01008 (LP015-10) in to brain.
  • Fig 2 IC50 determination of LI01008 for theinhibition of ⁇ Secretase enzyme.
  • the present invention provides a novel method of inhibiting the Beta-secretase enzyme by using Bis-O-demethylcurcumin (LI01008).
  • the present invention further discloses the prevention, management and treatment of Alzheimer's disease by the inhibition of Beta- secretase using Bis-O-demethylcurcumin.
  • the present invention further discloses the process of synthesizing Bis-O-demethylcurcumin.
  • the present invention provides a novel method of inhibiting the Beta-secretase enzyme by using Bis-O-demethylcurcumin (LI01008), also known as BDMC.
  • the present invention further discloses prevention, management and treatment of Alzheimer's disease by the inhibition of Beta-secretase using Bis-O- demethylcurcumin.
  • BDMC The efficacy of the brain transport of BDMC was evaluated by conducting in-vivo brain transport study. According to this study Bis-O-demethylcurcumin formulations crosses the blood-brain-barrier and showed good transportation into the brain cells (Fig. 1) and therefore, the BDMC has been evaluated for the inhibition of Peta-secretaseenzyme.
  • the inhibition of Peta-secretaseenzyme by bis-o- demethylcurcumin was performed by PanVera®'s BACE1 fluorescence resonance energy transfer (FRET) Assay Kit (Invitrogen part # 2985) (384-wells). According to this study, the IC50value of Bis-O-demethylcurcumin, for the inhibition of ⁇ -Secretase enzyme was found to be 1.301 ⁇ g/ml (Fig.2).
  • the efficacy of BDMC in reducing the amyloid plaques in transgenic Alzheimer's disease model (TgAPP (5XFAD)) mice was evaluated.
  • TgAPP transgenic Alzheimer's disease model
  • the Nontransgenic (NTg) and Transgenic(Tg) mice were divided into four groups.
  • Group I- NTg received vehicle (formulation without BDMC);
  • Group IV- TgAPP received composition 1.
  • Group III and Group-IV animals were treated once daily by gavage with Bis-O- demethylcurcumin formulation (equivalent to275 mg/kg body weight of BDMC) for 35 days.
  • the present invention discloses the prevention, management and treatment of Alzheimer's disease by the inhibition of Beta-secretase using Bis-O- demethylcurcumin or compositions comprising the same.
  • the present invention discloses the process of synthesizing Bis-O-demethylcurcumin. Accordingly, the process for synthesis of BDMC, which process comprises:
  • the Lewis acids may be selected from the group consisting of aluminum chloride, aluminum bromide, aluminum iodide and berrylium chloride.
  • the reaction may optionally be conducted in the presence of a catalyst such as alkali metal iodides in an organic solvent to obtain BDMC.
  • the BDMC thus obtained is isolated as a solid after employing conventional work up.
  • the current invention discloses the method of treatment of Alzheimer's disease by administering a therapeutically effective amount of Bis-O- demethylcurcumin or the compositions containing the same.
  • the invention provides compositions comprising therapeutically effective amount of BDMC and one or more drugs selected from B ACE inhibitors, acetyl cholinesterase inhibitors such as galantamine, rivastigmine, donepezil or memantine.
  • the invention describes the use of the said Bis-O- demethylcurcumineither alone or in combination/formulation with pharmaceutically acceptable excipients or ingredient/carriers thereof, for the preparation of medicament for prevent or treatment or management of Alzheimer's disease by inhibiting the Beta- secretase enzyme.
  • the present invention discloses administration of Bis-O- demethylcurcumin in pharmaceutically acceptable and suitable dosage forms such as solid, semisolid or liquid dosage forms.
  • the invention provides pharmaceutical compositions comprising a therapeutically effective amount of Bis-O-demethylcurcumin in association with one or more pharmaceutical excipients, for the management and treatment of Alzheimer's disease by the inhibition of Beta-secretase enzyme.
  • the therapeutically effective amount may ranges from 0.01 to 99.99% w/w of the composition/dosage form.
  • the invention provides pharmaceutical compositions comprising a therapeutically effective amount of Bis-O-demethylcurcumin optionally with at least one of natural anti-oxidants, phospholipids, lysophospholipids, lecithin, natural gums, inorganic salts or excipients.
  • Specific dosage forms for management and treatment of Alzheimer's disease by the inhibition of Beta-secretase using Bis-O-demethylcurcumin includes, for example, oral agents such as tablets, pellets,soft capsule, hard capsule, pills, granules, powders, emulsions, suspensions, syrups, inhalation aids, aerosol, transdermal delivery systems and other drug delivery systems; the parenteral agents such as injections, intravenous liquids, drops, suppositories and the like. These dosage forms may be prepared using suitable excipients using the methods known to a person skilled in pharmacy.
  • the solid composition will typically contain one or more inert diluents or edible carriers.
  • one or more of the following adjuvants may be present: binders such as carboxy methyl cellulose, ethyl cellulose, microcrystalline cellulose, or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, primogel, corn starch and the like; lubricants such as magnesium stearate or sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin, a flavoring agent such as peppermint, methyl salicylate or orange flavoring, and a coloring agent.
  • binders such as carboxy methyl cellulose, ethyl cellulose, microcrystalline cellulose, or gelatin
  • excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, primogel,
  • the other pharmaceutically accepted excipients or carrier such as Polysorbates, polyethylene glycols,lecithins, lysolecithins, cyclodextrins, Microcrystalline cellulose (MCC), methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropylethylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, poly(methyl methacrylate), polycarbophil, gelatin, alginate, poly(acrylic acid), polyethylene oxide and chitosan or a derivative thereof may also be used.
  • MCC Microcrystalline cellulose
  • HPMC hydroxypropylethylcellulose
  • HPMC hydroxypropylethylcellulose
  • sodium carboxymethylcellulose polyvinyl alcohol, polyvinylpyrrolidone, poly(methyl methacrylate), polycarbophil, gelatin, alginate, poly(acrylic acid), polyethylene oxide and chito
  • compositions that will be effective in the treatment of Alzheimer's disease or disorder or condition will depend on the nature/severity of the disorder or the condition, which can be determined by standard clinical techniques.
  • in vitro and in vivo assays may optionally be employed to help identify optimal dosage ranges.
  • the precise dose to be employed in the formulation will depend on the route of administration, and the seriousness or advancement of the diseased condition, and should be decided according to the practitioner and each patient's conditions.
  • Effective dosages may be extrapolated from dose response curves derived from in vitro or animal model test systems. For example an effective amount of the composition of the invention is readily determined by administering graded doses of the composition and observing the desired effect.
  • the BDMC may optionally be formulated into any food and drink forms such as solid food like chocolate or nutritional bars, semisolid food like cream or jam, or gel.
  • Contemplation was also made to formulate the product of the invention into a beverage and the like, such as refreshing beverage, coffee, tea, milk- contained beverage, lactic acid bacteria beverage, drop, candy, chewing gum, chocolate, gummy candy, yoghurt, ice cream, pudding, soft adzuki-bean jelly, jelly, cookie and the like.
  • Curcuma longa extract standardized to 95% total curcuminoids was subjected to column chromatography on silica column to obtain pure curcumin-1.
  • the curcumin-1 so obtained was demethylated using the above process to obtain bis-O-demethylcurcumin (1, BDMC);
  • composition -1 (LP015-10)
  • the evaluation of the transport of LI01008 in LP015-10 (Bis-O-demethylcurcumin formulation) across the blood-brain-barrier was performed in Wistar rats.
  • the test substances (LI015-10) were administered intravenously to the animals at a dose of lOmg kg body weight.
  • the animals were perfused vascularly with saline and sacrificed after 60, 90 and 120 mins respectively.
  • the whole brain was extracted and cryosectioned into 12 ⁇ size sections and visualized under confocal microscope.
  • the intensity of fluorescence of the samples under microscope is directly proportional to the concentration of test substance inside the brain cell and is correlative of the transport of the test substance into the brain cells.
  • LI01008 in LP015-10 (Bis-O-demethylcurcumin formulation) showed good transportation into the brain cells (Fig 1.).
  • LI01008(Bis-O-demethylcurcumin) was tested for its BACE-1 inhibitory activity by using PanVera®'s BACE1 fluorescence resonance energy transfer (FRET) Assay Kit (Invitrogen part # 2985) (384-wells).
  • FRET fluorescence resonance energy transfer
  • This kit provides a sensitive and efficient method for screening potential BACEl inhibitors.
  • This kit uses purified baculovirus-expressed BACEl and a new 'red' FRET peptide substrate based on the "Swedish” mutant.
  • Multiwell spectrofluorometer instrument capable of 530-545 nm excitation and 570-590 nm emission wavelengths was used for the assay (Molecular devices-spectra Max M5e).
  • the IC50value of LI01008 (Bis-0-demethylcurcumin)for the inhibition of ⁇ -Secretase enzyme was found to be 1.30 ⁇ g/ml (Fig.2).
  • mice transgenic Alzheimer's disease model mice
  • FgAPP transgenic Alzheimer's disease model mice
  • B6SJL-Tg APPSwFlLon, PSEN1 * M146L* L286V) 6799 Vas/Mmjax mice
  • Ng and Tg Nontransgenic(Tg)animals were divided into four groups with 3 to 4 mice in each group.
  • Group I- NTg received vehicle (formulation without LI01008); Group II- Tg received vehicle; Group III- NTg received LP015-10; Group IV- TgAPP received LP015-10.
  • Group III and Group-IV animals were treated once daily by gavage with Bis-O- demethylcurcumin formulation (equivalent to275 mg/kg BW of LI01008) for 35 days.
  • NTg control mice Fig 3A
  • LP015-10 treated NTg control mice Fig. 3B

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

Abstract

La présente invention concerne un nouveau procédé d'inhibition de l'enzyme bêta-sécrétase au moyen de bis-o-déméthylcurcumine. L'invention porte en outre sur la prévention, la prise en charge et le traitement de la maladie d'Alzheimer par l'inhibition de la bêta-sécrétase chez un patient au moyen de bis-o-déméthylcurcumine. L'invention a également trait au processus de synthèse de bis-o-déméthylcurcumine et à des compositions les comprenant.
PCT/IN2015/000232 2014-06-07 2015-06-05 Procédé d'inhibition de la bêta-sécrétase au moyen de bis-o-déméthylcurcumine pour la prévention, la prise en charge et le traitement de maladies neurodégénératives WO2015186144A2 (fr)

Applications Claiming Priority (2)

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IN2800/CHE/2014 2014-06-07
IN2800CH2014 2014-06-07

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WO2015186144A2 true WO2015186144A2 (fr) 2015-12-10
WO2015186144A3 WO2015186144A3 (fr) 2016-01-28

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109172538A (zh) * 2018-10-25 2019-01-11 安徽鼎旺医药有限公司 一种盐酸美金刚速溶微丸软胶囊

Family Cites Families (4)

* Cited by examiner, † Cited by third party
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US8784881B2 (en) * 2004-03-05 2014-07-22 Board Of Regents, The University Of Texas System Liposomal curcumin for treatment of diseases
US8021701B1 (en) * 2005-04-13 2011-09-20 Perry Stephen C Composition to retard the onset of symptoms of alzheimer's disease
EP1993365B1 (fr) * 2006-03-06 2013-05-08 The Regents of the University of California Formulations de curcuminoïde biodisponibles pour traiter la maladie d'alzheimer et d'autres troubles associés à l'âge
JP2011527340A (ja) * 2008-07-07 2011-10-27 ライラ ファーマシューティカルズ ピーブイティ．エルティディ． 経口活性クルクミノイド化合物

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109172538A (zh) * 2018-10-25 2019-01-11 安徽鼎旺医药有限公司 一种盐酸美金刚速溶微丸软胶囊

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