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WO2022035308A1 - Composition pour le traitement des maladies auto-immunes - Google Patents

Composition pour le traitement des maladies auto-immunes Download PDF

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Publication number
WO2022035308A1
WO2022035308A1 PCT/MY2021/050041 MY2021050041W WO2022035308A1 WO 2022035308 A1 WO2022035308 A1 WO 2022035308A1 MY 2021050041 W MY2021050041 W MY 2021050041W WO 2022035308 A1 WO2022035308 A1 WO 2022035308A1
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optionally substituted
silvestrol
compound
use according
medicament
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Inventor
Tiong Chia Yeo
Nyuk Fong KON
Michele MEJIN
Barbara NGIKOH @ NYIKOH
Sei Kong Gilbert LAU
Mohammad Farhan Darin AZRI
Jorim UJANG
May Fung Melissa CHANG
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Sarawak Government of State of Malaysia
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/58—Meliaceae (Chinaberry or Mahogany family), e.g. Azadirachta (neem)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/74—Rubiaceae (Madder family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant

Definitions

  • a composition for the treatment of autoimmune diseases is provided.
  • the present invention relates to a compound for the treatment of autoimmune diseases.
  • the present invention relates to the use of silvestrol, episilvestrol, and derivatives in treating autoimmune diseases with reduced risk of fungal infection.
  • Immune-mediated disease is characterized with uncontrolled activation of cell signaling proteins, leading to disturbed immune function and accelerated immune response. Certain autoimmune diseases are linked to inflammation due to increased T-lymphocyte and cytokines release.
  • Tumor Necrosis Factor Alpha is an essential cytokine for the formation and maintenance of granulomas, a key host defense mechanism against intracellular pathogens.
  • the cytokine plays a key role in early induction of chemokines and initial recruitment of leukocytes. It further promotes macrophage and phagosome activation, monocyte differentiation into macrophages, neutrophil recruitment and aggregation of leukocytes into functional granulomas to contain the infection.
  • TNF inhibitor is a group of medication used worldwide to treat autoimmune inflammatory conditions such as rheumatoid arthritis (RA), psoriatic arthritis, juvenile arthritis, inflammatory bowel disease (Crohn’s and ulcerative colitis), ankylosing spondylitis, and psoriasis. They reduce inflammation and stop disease progression by targeting TNF.
  • anti-TNF agents include Infliximab, Adalimumab, Etanercept, Golimumab, Certolizumab pegol.
  • One of the major risks of using anti-TNF therapy is the small but significant risk of serious opportunistic infections including fungal infections such as histoplasmosis and blastomycosis.
  • anti-TNF therapy has been associated with both primary and reactivated fungal infections.
  • the US FDA issued a “black box” warning with all anti-TNF therapies, alerting clinicians of the risks of certain fungal infections in patients treated with anti-TNF therapy.
  • Some common fungal infections associated with the use of anti-TNF therapy include Histoplasmosis, Coccidioidomycosis, Candidiasis, Aspergillosis, Blastomycosis, and Pneumocystosis. As such, there is an unmet medical need to develop a new anti-TNF therapy that does not carry the risks of fungal infections in patients treated for autoimmune inflammatory diseases.
  • Silvestrol is a natural compound isolated from the plants Aglaia sp. which are indigenous in Southeast Asia region. Silvestrol belongs to the flavaglines that have a cyclopenta[b]benzofuran core and a dioxane ether side chain.
  • the highly potent compound is known in the state of the art as anti-cancer agent. It is a specific inhibitor of translation initiation targeting the ATP-dependent DEAD-box RNA helicase elF4A, which hinders translation initiation of cap-dependent mRNA, in particular the oncogenic mRNAs with structured 5'-UTR. This capability renders its anti-cancer activity.
  • US 2017/0304261 disclosed the use of silvestrol together with vaccines for treating cancer such as EBV-driven lymphoma and nasopharyngeal carcinoma.
  • US Patent Application Publication No. US 20140255432 disclosed a treatment method using silvestrol for combating cancers.
  • PCT Application Publication No. WO 2017214024 disclosed an antibody-drug conjugate compound comprising silvestrol for use in treating cancers. It is not known in the state of the art to use silvestrol as an agent to suppress inflammation and/ or fungal infection.
  • each R 4 -R 10 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylacyl, optionally substituted cycloalkylacyl and a C-1 linked saccharide;
  • X is OR 8 or NR 9 R 10 ;
  • R 11 and R 12 are each independently hydrogen or, OR 4 and R 11 , and/or OR 5 and R 12 together form a methylenedioxy group;
  • Y is selected from the group consisting of optionally substituted phenyl, optionally substituted benzyl, optionally substituted benzoyl, optionally substituted C3-C8 cycloalkyl, optionally substituted CH 2 -(C3-C8 cycloalkyl), optionally substituted 5-6 membered heterocyclyl and optionally substituted CH 2 -(5-6 membered heterocyclyl).
  • the active compound used in the medicament is silvestrol or episilvestrol, or its derivative or analogs.
  • the autoimmune diseases which are targeted in the present invention include any one of psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile arthritis, inflammatory bowel disease, and ankylosing spondylitis.
  • the inflammatory bowel disease includes Crohn’s and ulcerative colitis.
  • the invention is a topical medicament which comprises Uncaria gambir incorporated as extract, enriched fraction or its bioactive compounds to provide analgesic and anesthetic effect.
  • the medicament can be delivered through any one of routes of administration of buccal, enteral, inhalable, intramuscular, intravenous, oral, nasal, nebulization, rectal, subcutaneous, sublingual, transdermal, and topical.
  • the medicament further comprises solid lipid nanoparticles or lipid carrier to improve permeation of the medicament across the skin.
  • Figure 1 shows the effect of silvestrol on TNF-a production by lipopolysaccharide (LPS)- activated RAW264.7 cells.
  • LPS lipopolysaccharide
  • Figure 2 shows the effect of silvestrol on G-CSF production by LPS-activated RAW264.7 cells
  • Cells are seeded at 50x10 3 cells per well and incubated for 2 hours for cells adherence. Cells are then treated with 25-1 OOnM of silvestrol in the presence of 1 pg/mL LPS for 24 h. TAK- 242 is served as positive control.
  • Data represent means ⁇ SD of triplicates.
  • Figure 3 shows the effect of silvestrol on the viability of RAW264.7 cell line performed by CytoTox 96® non-radioactive cytotoxicity assay kit.
  • the cells are treated with different concentrations of silvestrol for 24 h. Controls are obtained in the absence of compounds and LPS, respectively. No significant reduced viability at different concentrations. Data represent means ⁇ SD of triplicates.
  • Figure 4 shows the dose response effects of silvestrol on LPS-induced TNF-a release in human peripheral blood mononuclear cell (PBMC).
  • PBMC peripheral blood mononuclear cell
  • FIG. 4 shows the dose response effects of silvestrol on LPS-induced TNF-a release in human peripheral blood mononuclear cell (PBMC).
  • PBMC peripheral blood mononuclear cell
  • 10-80nM of silvestrol is then carried out in the presence of 0.1 pg/mL LPS for 24 h.
  • Bay11 -7082 is served as positive control.
  • Data represent means ⁇ SD of triplicates.
  • Figure 5 shows the dose response effects of silvestrol on LPS-induced IL-1p release in human PBMC.
  • PBMC is treated with 10-80nM of silvestrol.
  • Incubation is then carried out in the presence of 0.1 pg/mL LPS for 24 h.
  • Bay11 -7082 is served as positive control.
  • Data represent means ⁇ SD of triplicates.
  • Figure 6 shows the dose response effects of silvestrol on LPS-induced IL-6 release in human PBMC.
  • PBMC is treated with 10-80nM of silvestrol.
  • Incubation is then carried out in the presence of 0.1 pg/mL LPS for 24 h.
  • Bay11 -7082 is served as positive control.
  • Data represent means ⁇ SD of triplicates.
  • Figure 7 shows the dose response effects of silvestrol on LPS-induced IL-10 release in human PBMC.
  • PBMC is treated with 10-80nM of silvestrol.
  • Incubation is then carried out in the presence of 0.1 pg/mL LPS for 24 h.
  • Positive control is Bay1 1 -7082.
  • Data represent means ⁇ SD of triplicates.
  • Figure 8 shows the dose-independent effects of silvestrol on LPS-induced IFN-Y release in human PBMC.
  • PBMC is treated with 10-80nM of silvestrol.
  • Incubation is then carried out in the presence of 0.1 pg/mL LPS for 24 h.
  • Positive control is Bay1 1 -7082.
  • Data represent means ⁇ SD of triplicates.
  • Figure 9 shows the results of MTT assay in human PBMC after an overnight treatment with various concentrations of silvestrol. Controls are obtained in the absence of compounds and LPS, respectively. Data represent means ⁇ SD of triplicates.
  • Figure 10 shows the cell growth data (OD) of HaCaT cells (human skin keratinocyte) treated with silvestrol for 48 hrs. Data from treatments of silvestrol at concentration range from 0.038 to 382nM are used to calculate Gl 5 o value. Data represent means ⁇ SD of triplicates.
  • Figure 11 shows the dose response effects of silvestrol on TNF-a release in human PBMC induced with anti-CD3/ anti-CD28.
  • PBMC cells are sourced from two healthy donors. At 24 hours post stimulation with anti-CD3/ anti-CD28, PBMC is treated with 5-70nM of silvestrol for another 48 hours.
  • Bay1 1 -7082 at the same concentrations are included as positive control.
  • Data represent means ⁇ SD of triplicates.
  • Figure 12 shows the dose response effects of silvestrol on IL-12p70 release in human PBMC induced with anti-CD3/ anti-CD28.
  • PBMC cells are sourced from two healthy donors. At 24 hours post stimulation with anti-CD3/ anti-CD28, PBMC is treated with 5-70nM of silvestrol for another 48 hours.
  • Bay1 1 -7082 at the same concentrations are included as positive control.
  • Data represent means ⁇ SD of triplicates.
  • Figure 13 shows the dose response effects of silvestrol on IL-17A release in human PBMC induced with anti-CD3/ anti-CD28.
  • PBMC cells are sourced from two healthy donors. At 24 hours post stimulation with anti-CD3/ anti-CD28, PBMC is treated with 5-70nM of silvestrol for another 48 hours.
  • Bay1 1 -7082 at the same concentrations are included as positive control.
  • Data represent means ⁇ SD of triplicates.
  • Figure 14 shows the dose response effects of silvestrol on IL-17F release in human PBMC induced with anti-CD3/ anti-CD28.
  • PBMC cells are sourced from two healthy donors. At 24 hours post stimulation with anti-CD3/ anti-CD28, PBMC is treated with 5-70nM of silvestrol for another 48 hours.
  • Bay1 1 -7082 at the same concentrations are included as positive control.
  • Data represent means ⁇ SD of triplicates.
  • Figure 15 shows the dose response effects of silvestrol on IL-23 release in human PBMC induced with anti-CD3/ anti-CD28.
  • PBMC cells are sourced from two healthy donors. At 24 hours post stimulation with anti-CD3/ anti-CD28, PBMC is treated with 5-70nM of silvestrol for another 48 hours.
  • Bay1 1 -7082 at the same concentrations are included as positive control.
  • Data represent means ⁇ SD of triplicates.
  • Figure 16 shows the dose response effects of silvestrol on IL-22 release in human PBMC induced with anti-CD3/ anti-CD28.
  • PBMC cells are sourced from two healthy donors. At 24 hours post stimulation with anti-CD3/ anti-CD28, PBMC is treated with 5-70nM of silvestrol for another 48 hours.
  • Bay1 1 -7082 at the same concentrations are included as positive control.
  • Data represent means ⁇ SD of triplicates.
  • Figure 17 shows the percentage of viable cells in PBMC following 48 hours treatment with silvestrol.
  • the total cell and total viable cell numbers are obtained by staining with DAPI and analysed with volumetric analyzer.
  • Bay11 -7082 is included as positive control.
  • Other controls are obtained in the absence of compounds and anti-CD3/CD28, respectively.
  • Data represent means ⁇ SD of triplicates.
  • Figure 18 shows the alignment of elF4A protein sequences among selected fungal species, the elF4A from Aglaia stellatopilosa is included as reference.
  • Natural amino acid substitution of Phe163Leu and lle199Met seen in Aglaia plant enables them to escape from silvestrol's toxicity.
  • Other amino acids observed at position 163 and 199 of elF4A revealed that all fungal species included in the alignment may be subjected to silvestrol-mediated translation inhibition, except for Candida albicans and C. dubliniensis.
  • the amino acid position demonstrated is based on amino acid numbering in human elF4A1 .
  • Pichia kudriavzevii is formerly known as Candida krusei
  • Clavispora lusitaniae is also known as Candida lusitaniae.
  • Figure 19 shows LCMS profile of five fractions of ethanolic Uncaria gambir extract that are obtained by HPLC fractionation method.
  • LCMS measurement is performed using ESI-QTOF mass spectrometer (Impact II, Broker Daltonik) coupled to Dionex Ultimate 3000 UHPLC (Thermo Scientific). Mass spectrometry detection is performed in positive ion mode and scan range is 50-1000 m/z.
  • Figure 20 shows possible analgesic compounds found in Uncaria gambir, fraction 3. Catechin deemed majorly found in fraction 3. Other compounds including epicatechin, gambiriin A1 - A3, gambirflavan, procyanidins and kaempferol are deemed present in the ethanolic fractions.
  • A) The possible chemical constituents with monoisotopic mass of 291.0867 m/z, 579.1500 m/z and 580.1534 m/z are analyzed using SmartFormula.
  • Figure 21 shows the percentage viability of RAW264.7 (mouse macrophage) after 24 hrs treatment with various extracts of Uncaria gambir: A (Aqueous-Pulp from community); B (Aqueous-Decoction from community); C ( Aqueous- Freeze dried); D (Aqueous- Pulp); E (Methanol); F (Ethanol ACS grade); G (Ethanol food grade).
  • TAK-242 served as positive control. Data represent means ⁇ SD of triplicates.
  • Figure 22 shows COX-2 inhibitory activity of Uncaria gambir, silvestrol and its combined effects in murine macrophage RAW264.7.
  • U. gambir fraction is selected based on presence of catechin in LCMS analysis. Briefly, cells are seeded at 1.5 x 10 6 cells per well and incubated for 2 hours for cell adherence. Subsequently, cells are treated with samples in the presence of 1
  • COX Cyclooxygenase
  • treating should be construed to include the measure or action taken to a patient for controlling, suppressing or reducing risks, symptoms or pathogenesis associated with the diseases.
  • the present invention describes a medicament with an active compound having a cyclopenta[b]benzofuran core for treating autoimmune diseases.
  • the compound as utilized in the medicament is of Formula (I). wherein: each R 4 -R 10 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylacyl, optionally substituted cycloalkylacyl and a C-1 linked saccharide;
  • X is OR 8 or NR 9 R 10 ;
  • R 11 and R 12 are each independently hydrogen or, OR 4 and R 11 , and/or OR 5 and R 12 together form a methylenedioxy group;
  • Y is selected from the group consisting of optionally substituted phenyl, optionally substituted benzyl, optionally substituted benzoyl, optionally substituted C3-C8 cycloalkyl, optionally substituted CH 2 -(C3-C8 cycloalkyl), optionally substituted 5-6 membered heterocyclyl and optionally substituted CH 2 -(5-6 membered heterocyclyl).
  • the compound utilized in the medicament is silvestrol or episilvestrol, including its derivative or analogs, for treating autoimmune diseases including psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile arthritis, inflammatory bowel disease, and/ or ankylosing spondylitis
  • autoimmune diseases including psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile arthritis, inflammatory bowel disease, and/ or ankylosing spondylitis
  • the compound of silvestrol is of formula (ii) below.
  • the compound of the present invention is not to be limited to the sources of which it may be obtained.
  • the compound may be isolated from the natural sources such as from any parts of plants.
  • the compound may be produced synthetically, or derived from a synthetic process starting from a natural compound.
  • the active compound, silvestrol, episilvestrol or its analogue is isolated from the plants Aglaia sp., which is a tropical plant endemic to Sarawak, central Borneo, and Indonesia, and some pacific islands. More particularly, silvestrol and episilvestrol is isolated from Aglaia stellatopilosa.
  • Silvestrol and episilvestrol are diasteroisomers that are epimeric at 5”’. Both compounds contain cyclopenta[b]benzofuran with 1 ,4-dioxanyloxy, a pseudo-sugar moiety which has a significant beneficial impact on their bioactivities through discrete binding interaction with their molecular target. Therefore, both compounds exhibit similar mechanisms of action due to its similarity of structure.
  • Silvestrol has never been developed into any medication for treatment of autoimmune diseases including psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile arthritis, inflammatory bowel disease, and ankylosing spondylitis. It has been surprisingly found out the compound shows inhibitory effects on various pro- and anti-inflammatory cytokines which may include those involved in the pathogenesis of psoriasis, psoriatic arthritis, rheumatoid arthritis and ankylosing spondylitis. The inhibition is in nanomolar range which define the potency of the compound. In addition, silvestrol has been found to demonstrate antifungal activity.
  • the autoimmune diseases targeted in the present invention include psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile arthritis, inflammatory bowel disease, and ankylosing spondylitis.
  • the psoriasis diseases include but not limited to plaque psoriasis, guttate, inverse, pustular, erythrodermic arthritis.
  • the present invention relates to a method for treating autoimmune diseases by inhibiting Tumor Necrosis Factor with reduced risk of fungal infections by administering silvestrol or episilvestrol in a subject in need thereof.
  • TNF-a as a key trigger of innate inflammatory pathways, playing a role in promoting inflammation through synergism with other pro-inflammatory cytokines.
  • TNF-a, interleukin (IL)-1 , and IL-6 are the primary mediators among those involved in pro-inflammation stage.
  • IL-1 interleukin
  • IL-6 interleukin-6
  • TLR Toll-like receptor
  • LPS lipopolysaccharides
  • peptidoglycan pathogen-associated molecule
  • TLR plays a role in triggering both innate and adaptive immune response.
  • unregulated activation of TLR triggered by exogenous or endogenous ligands often brings about autoimmunity and inflammation.
  • the activated TLR signaling could trigger a number of downstream signaling cascades such as nuclear factor-kB (NF-kB), interferon (IFN) response factors (IRFs), and mitogen-activated protein (MAP) kinases which ultimately leading to T cell differentiation and regulatory cytokine production, including TNF-a, IL-6, IL-12 and IL-23.
  • downstream signaling cascades such as nuclear factor-kB (NF-kB), interferon (IFN) response factors (IRFs), and mitogen-activated protein (MAP) kinases which ultimately leading to T cell differentiation and regulatory cytokine production, including TNF-a, IL-6, IL-12 and IL-23.
  • TLR4 ligand LPS promotes IL-17 production by antigen-specific memory T cells through the induction of IL-1 and IL-23 production by dendritic cells (DC).
  • DC dendritic cells
  • Silvestrol and episilvestrol in the present invention have been found to show potent inhibition effect towards the production of these pro-inflammatory cytokines.
  • Silvestrol and episilvestrol may play a role in inhibiting TLR and, or NF-kB pathways and suppressing the elevated inflammatory signaling cascades associated from the pathways, thereby treating autoimmune diseases.
  • cytokines are associated with activation of Janus kinase/ signal transduction and activator of transcription (JAK-STAT) signaling pathway, which in turn can implicate in the pathogenesis of inflammatory and autoimmune diseases including psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile arthritis, inflammatory bowel disease, and ankylosing spondylitis.
  • JAK-STAT Janus kinase/ signal transduction and activator of transcription
  • signalling of IL-2, IL-4, IL-5 and IL-21 involves binding of the interleukins to the receptor coupled to JAK3.
  • the non-functional cytokine receptors and over-expression of STAT3 are associated with autoimmune diseases.
  • Silvestrol has been reported to reduce STAT1 and STAT3 expression via elF4A inhibition. Therefore, the inhibition of one or more cytokines is a result of reduced STAT1/3 expression. It is also indicated that STAT3 suppresses DC differentiation and activation by reducing the expression of co-stimulatory molecules on DC and STAT3-mediated inhibition of TLR- induced pro-inflammatory cytokines.
  • the immune-mediated inflammatory disorders such as psoriasis, psoriatic arthritis, rheumatoid arthritis and ankylosing spondylitis are pathogenically driven by T cell activation associated with the secretion of proinflammatory cytokines, including TNF-a, IL-17A, IL-22 and interferon IFN-Y.
  • IL-17 has been the major effector cytokine which acts on keratinocytes to stimulate production of proinflammatory cytokines and chemokines.
  • the differentiation of Th17 cell to produce IL-17 requires IL-6, IL-21 , IL-23 and IL-1 p. Inhibition of these cytokines may suspend Th 17 cell differentiation.
  • IL-10 represents a family of cytokine which possesses potent anti-inflammatory activity, or recently, studies have showed its role in immunosuppression, leading to decreased production of effector T cells to fight pathogen and thus allow viral persistence. Besides, IL- 10 can prevent DC maturation, and it can inhibit DC differentiation from mononuclear cell precursors. While silvestrol is showing inhibition of this cytokine, more progress may be made in blocking the effects of IL-10 such as prevention of immune suppression, reversal of DC dysfunction and restoration of immune responsiveness. Silvestrol’s effect on both pro- and anti-inflammatory cytokines suggest that it possesses immunomodulatory properties. Moreover, immunomodulatory effect of silvestrol on monocyte-derived macrophages and dendritic cells has been reported.
  • silvestrol promotes inflammatory markers in M1 monocyte-derived macrophages at low concentration, such as 5 nM, but the proinflammation response is impaired by reduced release of chemokines. Later at M2 macrophage, silvestrol promotes the anti-inflammatory potential by reducing the chemokine levels. [Blum, L., Geisslinger, G., Farnham, M. J., Grunweller, A., & Schiffmann, S. (2020). Natural antiviral compound silvestrol modulates human monocyte-derived macrophages and dendritic cells. J Cell Mol Med., 24(12): 6988-6999.]
  • the same medicament of the present invention is effective for treating, preventing, or reducing risk of fungal infections.
  • the medicament could suppress the opportunistic fungal infection which may otherwise arise, for example, as a result of treatment by other type of drugs targeting the immune system which renders it susceptible to fungal infections.
  • the use of the medicament is applicable for treating fungal infections in general.
  • the fungal infections targeted include but not limited to infections of any one of Histoplasma capsulatum, Coccidioides immitis, C. posadasii, Candida tropicalis, C. auris, C. maltosa, C. duobushaemulonis, C. glabrata, C. famata, Aspergillus niger, A. kawachii, A. clavatus, A. fischeri, A. oryzae, A. fumigatus, A. nidulans, A.
  • Rocaglates a class of natural compound isolated from plants of the genus Aglaia where the silvestrol and episilvestrol are derived from, has been showed to exert similar mode of action by causing translation inhibition. It has been reported that these Rocaglates targeted the Tif and mediates inhibition of translation in Candida auris, thereby activating a cell death program. This, however, is not observed in its relative pathogen, C. albicans. The species only showed rocaglates-mediated translation inhibition through single point mutation at drug-binding domain of its Tif1. [Iyer, K. R., Whitesell, L., Porco, J. A., Henkel, T., Brown, L.
  • sequence alignment of elF4A among fungi species and silvestrol- producing plant, A. stellatopilosa deduced that silvestrol is active toward a wide range of fungal species.
  • These residues have been the silvestrol-mRNA binding site which render compound activity.
  • yeast mutagenesis screen mutations of yeast elF4A at Phe151 Leu/ Phe151 Ser (correspond to Phe163Leu in human) and lso187Met (correspond to lle199Met in human) confer insusceptibility to silvestrol-mediated cell death.
  • this finding identified the two residues as critical site to deduce wide range of silvestrol-susceptible fungi.
  • the elF4A alignment revealed that all fungal species included in the alignment fall within silvestrol- susceptible group, except for Candida albicans and C. dubliniensis. This is similar to what was observed in a screening assay of C. auris and C. albicans as mentioned above. All in all, this validates the silvestrol-elF4A drug target activities based on elF4A sequence in identifying silvestrol-susceptible species.
  • the composition of the medicament further comprises Uncaria gambir incorporated as extract, enriched fraction or its bioactive compound, which provides anesthetic or analgesic effects for soothing irritation and discomfort which may be caused by the disease.
  • Uncaria gambir incorporated as extract, enriched fraction or its bioactive compound, which provides anesthetic or analgesic effects for soothing irritation and discomfort which may be caused by the disease.
  • the plant extract elicits a numbing sensation when applied to the skin and may relieve itchiness on skin lesions.
  • the plant is used as painkiller or analgesic agent by the local community of Sarawak, a Malaysian state on Borneo. According to the local ethnic at Karangan Mong, it is applied to the gums for numbing sensation during toothache and applied to the itchy skin for soothing effect.
  • the resin from the leaves is excreted from rubbing the leaves and dried for storage.
  • Cyclooxygenase is an enzyme responsible for the synthesis of prostaglandins from arachidonic acid. Inflammatory prostaglandins play a role in pain perception and cause vasodilation which can result in clinical feature of skin inflammation.
  • the isoenzyme, COX-2 is expressed during inflammation and is involved in the pathophysiologic processes such as pain, inflammation and fever. Inhibition of COX-2 prevents the conversion of arachidonic acid into inflammatory prostaglandins Therefore, COX-2 inhibitor can provide relief from the symptoms of inflammation with analgesic efficacy.
  • the medicament can be provided through any one of routes administration of buccal, enteral, inhalable, intramuscular, intravenous, oral, nasal, nebulization, rectal, subcutaneous, sublingual, transdermal, and topical.
  • the medicament is provided in the form of ointment for topical application.
  • the medicament may comprise any suitable pharmaceutical acceptable excipient, carrier or supplementary substance. Avoiding toxic level of the active compound is achievable via encapsulation in carrier.
  • the pharmaceutical carrier comprises liposome in nanoscale.
  • the liposome is used as drug delivery platform due to its potential in therapeutic action.
  • the liposome can be manipulated for long-circulating, triggered release by external factors or directed site of action, hence releasing drug in a more controlled manner. Liposome enhances dermal drug delivery and accumulation at target site suitable for use in topical medicament.
  • Silvestrol shows potent suppression effects toward pro- and anti-inflammatory cytokines. This is demonstrated in cell-based assays using lipopolysaccharide (LPS)-induced mouse macrophage (RAW264.7) and human peripheral blood mononuclear cell (PBMC).
  • LPS lipopolysaccharide
  • PBMC peripheral blood mononuclear cell
  • the suppressed cytokines include but not limited to TNF-a, G-CSF, IL-1p, IL-6, and IL-10.
  • the reduction of TNF-a and G-CSF levels in RAW264.7 is observed at 50 - 100 nM in dose-dependent manner.
  • human PBMC the reduction of TNF-a is seen from 70 nM, as shown in Figure 4.
  • the secretion of IL-6 is also significantly reduced in response to silvestrol starting at 20nM, as shown in Figure 6.
  • the reduction of IL-1 p and IL- 10 levels are observed from 10nM, as shown in Figure
  • the toxicity of silvestrol is assessed by using CytoTox 96® non-radioactive cytotoxicity assay kit (for RAW264.7 assay) and MTT assay (for PBMC assay). The results are shown in Figures 3 and 9 respectively. This reveals no toxicity up to at least 100nM silvestrol. The results demonstrated in vitro efficacy range from 20nM up to at least 80nM within which silvestrol can be applied to efficiently inhibit inflammatory cytokines without toxicity effects.
  • TNF-a, IL-1 and IL-6 are the primary mediators of immune response activated by Toll-like receptor (TLR) signaling pathways. Inhibition of silvestrol towards these cytokines suggesting that silvestrol may play a role in TLR inhibition and thus contribute to suppression of pathogenesis at the early stage of inflammatory disease.
  • TLR Toll-like receptor
  • silvestrol may play a role in TLR inhibition and thus contribute to suppression of pathogenesis at the early stage of inflammatory disease.
  • the effect on IFN-gamma is not in dose-dependent inhibition, as shown in Figure 8.
  • IL-17 which acts alone or synergistically with TNF-a in inducing inflammatory tissue responses.
  • Pro-inflammatory cytokine, IL-23 helps in differentiation of Th17 cells, which in turn produces IL-17 and IL-22.
  • IL-17 Pro-inflammatory cytokine
  • IL-22 Pro-inflammatory cytokine
  • IL-23 helps in differentiation of Th17 cells, which in turn produces IL-17 and IL-22.
  • This uncontrolled cascade of signaling pathway of IL-23/IL-17 plays a crucial role in the autoimmune diseases and particularly in pathogenesis of psoriasis.
  • the differentiation of Th17 cell requires IL-1 p, IL-6, IL-21 and IL-23, inhibition of these cytokines may block the differentiation of Th17 cell. A lack of any of these cytokines could impair IL-17 production.
  • Silvestrol also demonstrates potent inhibition effects toward these pro-inflammatory cytokines other than TNF-a.
  • the active compound of Formula (I), or silvestrol or episilvestrol treats autoimmune diseases by inhibiting secretion of TNF-a and other pro-inflammatory cytokines.
  • Silvestrol has been evaluated on the suppression of IL-12p70, IL17A, IL-17F, IL-23, IL-22 and TNF-a following stimulation with anti-CD3/ anti-CD28 coated Dynal beads in PBMC from two normal human donors. Differences in cytokine secretion between donors are seen, but this is not unexpected.
  • IL12p70 is a key cytokine for the induction of IFN-Y in both T cells and NK cells, thereby supporting a Th1 immune responses.
  • Silvestrol causes a significant reduction in IL-12 levels from 20 - 70 nM in Donor 2, but IL-12 is not induced in Donor 1 , as shown in Figure 12.
  • IL-17 contributes to various lesions and chronic inflammation that are produced by Th17 cells.
  • IL-17A and IL-17F are co-expressed by the same immune cell types. Both play a similar function and act synergistically as inflammatory mediators.
  • silvestrol causes a significant reduction of IL-17A from 30 - 70 nM in Donor 1 only.
  • the induction of IL-17A in Donor 2 is more modest and although there was a reduction in the cytokine levels at 30 - 70 nM, this reduction is not significant, as shown in Figure 13.
  • Silvestrol also causes a significant reduction in IL-17F in both donors.
  • IL-22 is also produced by Th17 cells. IL-22 acts cooperatively with IL-17A and IL-17F to regulate local tissue inflammation through the induction of cytokine and chemokine expression. However, it has shown that the function of IL-22 is cell type dependent. IL-22 did not enhance the expression of chemokines from primary keratinocytes. Further, it has shown that IL-22 in combination with IL-17A and IL-17F enhance the expression of antimicrobial peptides by primary keratinocytes. The essential role of IL-22 in vivo remained not well understood. Importantly, the effect on TNF-a is consistently demonstrated, the reduction is observed from 30 - 70 nM in both donors, as shown in Figure 11. There is no decrease in viability in either donor in response to treatment over the time course of the experiment, as shown in Figure 17.
  • silvestrol is effective towards inflammatory autoimmune diseases that are pathogenically driven by TNF-a and I L-23/I L- 17 such as psoriasis and psoriatic arthritis.
  • TNF- a drives the production of IL-23 and subsequently activates the IL-17-producing lymphocytes.
  • IL-17 acts alone or synergistically with TNF-a to upregulate many keratinocyte gene, inducing the production of psoriasis-related proteins such as hBD2, LCN2, S100 and LL37/cathelicidin. It has been proven that blocking IL-23/IL-17 axis showed significant effectiveness in the suppression of psoriasis disease.
  • silvestrol has been formulated into topical ointment base composition containing 50% white soft paraffin, 30% emulsifying wax and 20% liquid paraffin.
  • Levigation or cold fusion method is used for silvestrol incorporation to avoid heating process that may lead to different forms of silvestrol.
  • Ointment prepared in this method shows solubilized particles of the compound in the base when seen under the microscope.
  • the ointment is applied to the rat for acute dermal toxicological test following OECD Guideline for Testing Chemical, Guideline 402 (2017).
  • the ointments have been tested at 0.0005mg/g, 0.002mg/g and 0.01 mg/g. The results are shown in Tables 1 and 2 below.
  • Table 1 The effect of dermal application of different doses of silvestrol ointment on female rats body weight, toxic symptoms and internal organs.
  • Rat DOSE Weight of rat (g) Onset of Toxic Observation no. (pg/g) week 0 week 1 week 2 at Death Symptoms on major death (h) organs
  • Table 2 The cage side observation of dermal application of silvestrol ointment on female rats.
  • N Normal The silvestrol ointment is further evaluated for skin permeability using Franz cell system with porcine ear skin. Porcine ear skin is stripped to remove the stratum corneum which mimics the diseased skin. It shows higher percentage of permeation through the stripped skin compared to the full thickness skin ( ⁇ 1.5 fold). Permeation profile of silvestrol ointment at 1 mg/g shows 29.3% (2.93 ⁇ 0.63pg/cm 2 ) of silvestrol permeated, 5.5% (0.55 ⁇ 0.09pg/cm 2 ) left in the skin and 38.9% left on the skin.
  • silvestrol For ointment at 0.1 mg/g, 10.8% (0.108 ⁇ 0.006pg/cm 2 ) of silvestrol permeated, 8.7% (0.087 ⁇ 0.019pg/cm 2 ) left in the skin and 71 .0% left on the skin. More silvestrol is permeated through the stripped skin type due to the removal of stratum corneum which acts as a barrier to restrict permeation of compounds through the skin. In spite of these differences, the amount of silvestrol left in the skin remains similar for both skin types. This is likely characterized by the type of ointment base used.
  • IMQ imiquimod
  • Dosing regimen is twice daily, estimated from PK profile of silvestrol in mice through intravenous and intraperitoneal route of administration, which are 7.6 hr and 1.9 hr, respectively (based on study by Ohio State University).
  • Clinical psoriasis area and Severity Index (PASI) for erythema, scaling and thickening of the skin will be characterized.
  • Skin from the back of mouse will be harvested for immunohistochemistry staining for CD3, CD4, CD8, CD1 1c, MHC-II, Gr1/Ly6G, involucrin, pDC and macrophages.
  • Ear punch biopsies will be harvested for cytokines measurement (TNF-a, IL-6, IL-12, IL-23, IL-17A and IL-17F).

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Abstract

La présente invention concerne l'utilisation d'un composé dans la fabrication d'un médicament pour traiter les maladies auto-immunes en inhibant le facteur de nécrose tumorale avec un risque réduit d'infections fongiques, le composé étant de formule (1), où : chaque R4-R10 est choisi indépendamment dans le groupe constitué par l'hydrogène, un groupe alkyle éventuellement substitué, un groupe acyle éventuellement substitué, un groupe aryle éventuellement substitué, un groupe arylalkyle éventuellement substitué, un groupe cycloalkylalkyle éventuellement substitué, un groupe arylacyle éventuellement substitué, un groupe cycloalkylacyle éventuellement substitué et un saccharide lié à C-1; X est OR8 ou NR9R10; R" et R12 sont chacun indépendamment un atome d'hydrogène ou, OR4 et R", et/ou OR 5 et R12 forment ensemble un groupe méthylènedioxy; et Y est choisi dans le groupe constitué par un groupe phényle éventuellement substitué, un groupe benzyle éventuellement substitué, un groupe benzoyle éventuellement substitué, un groupe cycloalkyle en C3-C8 éventuellement substitué, un groupe CH2-(cycloalkyle en C3-C8) éventuellement substitué, un groupe hétérocyclyle à 5-6 chaînons éventuellement substitué et un groupe CH2-(hétérocyclyle à 5-6 chaînons) éventuellement substitué. Le médicament peut en outre comprendre de l'Uncaria gambir incorporé sous forme d'extrait, de fraction enrichie ou de ses composés bioactifs, pour fournir un effet anesthésique ou analgésique. Dans un mode de réalisation particulier, le composé est le silvestrol et est utilisé pour traiter le psoriasis.
PCT/MY2021/050041 2020-08-11 2021-05-28 Composition pour le traitement des maladies auto-immunes Ceased WO2022035308A1 (fr)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
US6710075B2 (en) * 2000-07-05 2004-03-23 The Government Of The State Of Sarawak, Malaysia Therapeutic compounds and methods
EP1693059A1 (fr) * 2005-02-22 2006-08-23 Deutsches Krebsforschungszentrum Utilisation des dérivés de rocaglamide en tant qu'inhibiteurs NF-À-spécifiques pour le traitement de certaines maladies inflammatoires
WO2013016658A1 (fr) * 2011-07-27 2013-01-31 The Ohio State University Research Foundation Silvestrol, analogues du silvestrol et leurs utilisations

Patent Citations (3)

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US6710075B2 (en) * 2000-07-05 2004-03-23 The Government Of The State Of Sarawak, Malaysia Therapeutic compounds and methods
EP1693059A1 (fr) * 2005-02-22 2006-08-23 Deutsches Krebsforschungszentrum Utilisation des dérivés de rocaglamide en tant qu'inhibiteurs NF-À-spécifiques pour le traitement de certaines maladies inflammatoires
WO2013016658A1 (fr) * 2011-07-27 2013-01-31 The Ohio State University Research Foundation Silvestrol, analogues du silvestrol et leurs utilisations

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LI PAN, JOHN L. WOODARD, DAVID M. LUCAS, JAMES R. FUCHS, A. DOUGLAS KINGHORN: "Rocaglamide, silvestrol and structurally related bioactive compounds from Aglaia species", NATURAL PRODUCT REPORTS, ROYAL SOCIETY OF CHEMISTRY, GB, vol. 31, no. 7, 1 January 2014 (2014-01-01), GB , pages 924, XP055371866, ISSN: 0265-0568, DOI: 10.1039/c4np00006d *
LI PING, ZHENG YING, CHEN XIN: "Drugs for Autoimmune Inflammatory Diseases: From Small Molecule Compounds to Anti-TNF Biologics", FRONTIERS IN PHARMACOLOGY, vol. 8, 12 July 2017 (2017-07-12), XP055908461, DOI: 10.3389/fphar.2017.00460 *
PATTON JOHN T., LUSTBERG MARK E., LOZANSKI GERARD, GARMAN SABRINA L., TOWNS WILLIAM H., DROHAN CALLIE M., LEHMAN AMY, ZHANG XIAOLI: "The translation inhibitor silvestrol exhibits direct anti-tumor activity while preserving innate and adaptive immunity against EBV-driven lymphoproliferative disease", ONCOTARGET, vol. 6, no. 5, 20 February 2015 (2015-02-20), pages 2693 - 2708, XP055908446, DOI: 10.18632/oncotarget.2098 *
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