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WO2018199633A1 - Composition pharmaceutique destinée à prévenir ou à traiter des maladies liées au vieillissement, contenant un dérivé de décursine comme principe actif - Google Patents

Composition pharmaceutique destinée à prévenir ou à traiter des maladies liées au vieillissement, contenant un dérivé de décursine comme principe actif Download PDF

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Publication number
WO2018199633A1
WO2018199633A1 PCT/KR2018/004812 KR2018004812W WO2018199633A1 WO 2018199633 A1 WO2018199633 A1 WO 2018199633A1 KR 2018004812 W KR2018004812 W KR 2018004812W WO 2018199633 A1 WO2018199633 A1 WO 2018199633A1
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Prior art keywords
slc
progerin
aging
formula
preventing
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Ceased
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PCT/KR2018/004812
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English (en)
Korean (ko)
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WO2018199633A4 (fr
Inventor
박범준
송규용
오유석
이지현
윤은주
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PRG S&Tech Inc
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PRG S&Tech Inc
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Priority claimed from KR1020180045593A external-priority patent/KR102070328B1/ko
Application filed by PRG S&Tech Inc filed Critical PRG S&Tech Inc
Priority to US16/605,802 priority Critical patent/US11008332B2/en
Priority to JP2019558763A priority patent/JP6826674B2/ja
Priority to CN201880027751.9A priority patent/CN110573514B/zh
Priority to EP18791502.0A priority patent/EP3617211B1/fr
Publication of WO2018199633A1 publication Critical patent/WO2018199633A1/fr
Publication of WO2018199633A4 publication Critical patent/WO2018199633A4/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel decusin derivative and a composition for preventing or treating aging-related diseases containing the same as an active ingredient.
  • HGPS Hutchinson Gilford progria syndrome
  • HGPS is a very rare autosomal dominant genetic disease caused by a silent mutation of G608G of Lamin A (LMN A).
  • LN A Lamin A
  • the mutation produces a new cleavage donor site and produces a selective cleavage site product, Progerin (Prg), in which the 50 amino acids of the C-terminal domain of Lamin A are deleted.
  • progerin leads to morphological changes such as nuclear membrane irregularity or reduction of nuclear-cytoplasmic lamin A. Inhibition of progerin leads to reduction of nuclear deformation, which has been identified as a major factor of HGPS.
  • the present invention provides a novel compound that inhibits the binding of progerin and lamin A, and to provide a composition comprising the compound as an active ingredient as a pharmaceutical composition for preventing or treating aging-related diseases such as premature mania.
  • the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutical composition for preventing or treating aging-related diseases containing a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a cosmetic composition for preventing or improving wrinkles comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • novel compounds according to the present invention exhibited excellent progerin expression and inhibitory effect of progerin and lamin A binding in premature ejaculation-induced cells and animal models.
  • oral administration resulted in progerin and lamin levels similar to intraperitoneal injection.
  • the compounds of the present invention are aging such as Hutchinson Gilford progria syndrome (HGPS) and Werner syndrome. It can be effectively used in the treatment of related diseases, the novel compounds of the present invention can be provided as a cosmetic composition for preventing or improving wrinkles as it has been found to increase collagen production of skin cells.
  • FIG. 1 is a result of confirming the inhibitory effect of progerin-lamin A binding
  • Figure 1A in vivo PK analysis of JH4 confirmed the suppression of aging phenotype in progeria model mice injected with JH4 intraperitoneally, but very much when PO treatment Disappearing quickly is a confirmed result.
  • Figure 1B is a schematic diagram showing the formation of JH4 derivatives, in order to suppress the rapid degradation in vivo, the side chain was replaced with amino bonds (JH010) or ether bonds (SLC-D011) to confirm the synthesized JH4 derivative compounds.
  • FIG. 1C shows the effect of JH4 derivatives inhibiting Lamin A (LMNA) and progerin interactions.
  • LMNA Lamin A
  • FIG. 1D is a result of confirming the progerin expression inhibitory effect of SLC-D011 (D011) through progerin expression analysis, each compound was treated with progerin-transformed 293 cells 24 hours and confirmed progerin expression, JH4 Or D011 clearly shows an inhibitory effect on progerin expression compared to JH010.
  • 1E shows the effect of D011 on improving nuclear morphology and inhibiting progerin expression, incubating the compound with HGPS cells (AG03198, 10-year-old female; AG03199; 10-year-old female) for 48 hours.
  • FIG. 2 shows the significant in vivo effects of SLC-D011.
  • FIG. 2A shows the in vivo PK analysis of JH010 and SLC-D011. Both compounds showed an appropriate PK profile, and BA showed bioavailability.
  • Figure 2B is a result of confirming the human ERG (hERG) inhibitory effect of SLC-D011, as the hERG inhibitory effect is confirmed in JH010, as a result of confirming the effect of SLC-D011 on hERG, SLC-D011 shows hERG inhibitory effect Did.
  • hERG human ERG
  • FIG. 2C shows the effect of SLC- D011 on prolonging lifespan of Lmna G609G / G609G , a progeria model mouse, compared with SLC-D011 20 compared with an average lifespan of 14.8 weeks (maximum lifespan 15 weeks).
  • Intraperitoneal injection of mg / kg twice a week confirmed that life was extended to 19.5 weeks (up to 21 weeks), and SLC- D011 was injected into 5-week-old Lmna G609G / G609G mice.
  • Figure 2D confirms the overall morphology of the 10-week-old Lmna G609G / G609G mice injected, it was confirmed that mice injected with SLC-D011 at the same age is larger than the control mice.
  • FIG. 2E shows the effect of SLC- D011 on the lifespan of Lmna wt / G609G mice.
  • the injected group was found to have an extended average lifespan of up to 65 weeks, with the injection starting at 43 weeks of age.
  • FIG. 2F shows the entire form of Lmna wt / G609G mice injected with D011 , although weak and weak in 45-week-old Lmna wt / G609G mice, despite the same age as vehicle mice.
  • FIG. 3 shows the effect of oral administration of SLC-D011 on premature aging.
  • FIG. 3A shows that SLC-D011 is very hydrophobic and thus does not dissolve in aqueous solution.
  • the solubility was confirmed in the solution already used in the pharmaceutical formulation, and the solution based on the olein (monoolein) (right) was selected as the dissolution solution.
  • 3B shows the stability of SLC-D011, which requires heating and sonication at 80 ° C. for complete dissolution, but SLC-D011 shows the same pattern as the original compound for heating and sonication as a result of LC-MS analysis. Not confirmed.
  • Figure 3D confirms the increase in the weight of Lmna G609G / G609G mice following oral administration of SLC- D011, it was confirmed that the weight of the treated mice compared with the vehicle group was increased by 35%.
  • Figure 3E is the result of confirming the overall shape of the 8-week-old SLC-D011 treated mice, the results confirmed that the body size of the treated mouse is larger than the vehicle-mouse.
  • FIG. 4A shows that HGPS cells transformed with each vector for 48 hours were stained with H3K9me3 antibody and stained with H3K9me3 antibody.
  • H3K9me3 expression was confirmed in HGPS cells transformed with human WRN (hWRN), while H3K9me3 expression was not observed in HGPS cells transformed with mouse WRN (mWRN).
  • Figure 4B shows the human specific dual region involved in progerin-WRN binding, wherein the beads bound to GST WRN-R1 (non-repeatable peptide) and WRN-R2 (redundant peptide) were GFP-LmnA or progerin traits. Incubated with the injected 293 cell lysates and centrifuged to perform immunoplow assay, followed by Western blot analysis confirming the bound GFP protein.
  • Figure 4C shows the effect of WRN-R2 inhibits the interaction of Lamin A with progerin, 293 lysate and GRN-Lamine A transformed bead-bound GST-progerin with WRN-R1 or R2 The incubation in the presence or absence of the present condition, it was confirmed that the amine A-progerin interaction was clearly reduced in the group to which the recombinant WRN-R2 is added.
  • 4D shows the effect of recombinant WRN-R2 peptides inducing H3K9me3 and improving nuclear malformations after 24 hours of insertion of WRN-R1 and R2 peptides into HGPS cells using protein transport reagents.
  • H3K9me3 expression was increased in the cells and the nuclear shape was confirmed.
  • 4E shows that H3K9me3 expression was induced by progerin removal in Werner syndrome (WS) patient cells.
  • WS cells were transformed with si-control or si-progerin for 48 hours and H3K9me3.
  • Staining with antibody and DAPI nuclear staining
  • Figure 4F is a result confirming the effect of the SLC-D011 to improve the nuclear malformation of WS cells, incubated for 48 hours WS cells and SLC-D011 and confirmed by staining with Lamin A / C antibody and DAPI.
  • 4G shows the effect of induction of H3K9me3 expression by SLC-D011 in WS cells after 48 hours of incubation of SLC-D011 with WS cells, and the WS cells expressing very low H3K9me3 by SLC-D011 treatment. It was confirmed that H3K9me3 expression was clearly induced.
  • FIG. 5 is a result of confirming the effect of SLC-D011 in human skin keratinocytes HaCaT cells and fibroblasts
  • Figure 5A was treated with SLC-D011 in HaCaT cells after incubation for 24 hours confirmed the amount of collagen 1A expression in HaCaT cells
  • FIG. 5B shows collagen 1A after 24 hours incubation with SLC-D011 in normal fibroblasts 9N (GM 00038, 9-year-old female) and N46 (AG13299, 46-year-old male). Western blot analysis results confirmed the expression level.
  • the present invention can provide a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention can provide a pharmaceutical composition for preventing or treating aging-related diseases containing a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is (7S)-(+)-8,8-dimethyl-7- (3-phenyl-allyloxy) -7,8-di Hydro-6H-pyrano [3,2-g] chromen-2-one ⁇ (7S)-(+)-8,8-Dimethyl-7- (3-phenyl-allyloxy) -7,8-dihydro- 6H-pyrano [3,2-g] chromen-2-one (SLC-D011) ⁇ .
  • the aging-related disease may be premature ejaculation.
  • the premature ejaculation may be selected from the group consisting of Werner syndrome and Hutchinson Gilford syndrome.
  • the compound represented by Formula 1 and a pharmaceutically acceptable salt thereof may inhibit the binding between progerin and lamin A.
  • the pharmaceutical composition is any one selected from the group consisting of injections, granules, powders, tablets, pills, capsules, suppositories, gels, suspensions, emulsions, drops or solutions according to conventional methods
  • the pharmaceutical composition is a suitable carrier, excipient, disintegrant, sweetener, coating agent, swelling agent, lubricant, glidant, flavoring agent, antioxidant, buffer, bacteriostatic agent, which are commonly used in the preparation of pharmaceutical compositions, It may further comprise one or more additives selected from the group consisting of diluents, dispersants, surfactants, binders and lubricants.
  • the carriers, excipients and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil can be used, and solid preparations for oral administration include tablets, pills, powders, granules, capsules.
  • solid preparations may be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin and the like in the composition.
  • excipients such as starch, calcium carbonate, sucrose or lactose, gelatin and the like
  • lubricants such as magnesium styrate and talc may also be used.
  • Oral liquid preparations include suspensions, solvents, emulsions, syrups, and the like, and may include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
  • Witsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like may be used as the base material of the suppository.
  • the pharmaceutical composition is intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, intrasternal, transdermal, nasal, inhaled, topical, rectal, oral, intraocular or intradermal Via the route can be administered to the subject in a conventional manner.
  • the preferred dosage of the compound represented by Formula 1 may vary depending on the condition and weight of the subject, the type and extent of the disease, the drug form, the route of administration, and the duration, and may be appropriately selected by those skilled in the art. According to one embodiment of the present invention, but not limited thereto, the daily dosage may be 0.01 to 200 mg / kg, specifically 0.1 to 200 mg / kg, more specifically 0.1 to 100 mg / kg. Administration may be administered once a day or divided into several times, thereby not limiting the scope of the invention.
  • the 'subject' may be a mammal including a human, but is not limited thereto.
  • the present invention can provide a cosmetic composition for preventing or improving wrinkles comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • the compound represented by Chemical Formula 1 and its pharmaceutically acceptable salt may improve collagen production in keratinocytes and fibroblasts.
  • the cosmetic composition may include conventional auxiliaries such as stabilizers, solubilizers, vitamins, pigments and flavors, and a carrier, in addition to the compound represented by Formula 1 as an active ingredient.
  • auxiliaries such as stabilizers, solubilizers, vitamins, pigments and flavors, and a carrier, in addition to the compound represented by Formula 1 as an active ingredient.
  • the cosmetic composition may be prepared in any formulation conventionally prepared in the art, for example, solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, oils, powder foundations, emulsion foundations, It may be formulated as a wax foundation and spray, but is not limited thereto. More specifically, it may be prepared in the form of a sun cream, a flexible lotion, a convergent lotion, a nourishing lotion, a nourishing cream, a massage cream, an essence, an eye cream, a pack, a spray or a powder.
  • the formulation is a paste, cream or gel
  • animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicon, bentonite, silica, talc or zinc oxide may be used as a carrier component.
  • the formulation is a powder or a spray
  • lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used, in particular in the case of a spray additionally chlorofluorohydrocarbon, propane / butane Or propellants such as dimethyl ether.
  • a solvent, solubilizer or emulsion is used as carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 Fatty acid esters of butylglycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan.
  • liquid carrier diluents such as water, ethanol or propylene glycol
  • suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters, microcrystalline cellulose as carrier components , Aluminum metahydroxy, bentonite, agar or tracant and the like can be used.
  • optical rotations were measured on a JASCO DIP-360 automatic digital polarimeter, and the purity of the chiral material was measured by HPLC (Shimadzu LC-6AD, Japan), column (CHIRACEL OD-H 0.46 cm ⁇ x 25 cm, DAICEL). CHEMICAL IND., Co. Osaka, Japan).
  • Silica gel for the material separation was used SiliaFlash® P60 (SILICYCLE, 230 ⁇ 400mesh), thin film TLC plate was used TLC silica gel 60 F254 (MERCK).
  • Solvents and reagents used in the synthesis of materials were purchased from Sigma-Aldrich, Fluka, TCI, Junsei, Duksan pure chemical, SK Chemical and SAMCHUN chemical.
  • Diisobutylalumminium hydride 1M solution (DIBAL-H; 1M solution in hexane, 74 ml, 74.0 mmol, 3 eq) was slowly added dropwise to the reaction solution over 30 minutes, and then the reaction temperature was adjusted to 0 ° C. Methanol (22 ml) was slowly added dropwise while stirring to raise for 1 hour.
  • DIBAL-H 1M solution in hexane, 74 ml, 74.0 mmol, 3 eq
  • reaction solution was transferred to room temperature, stirred for 30 minutes, and a saturated aqueous solution of Rochelle's salt (88 ml) was added thereto.
  • the reaction mixture was stirred vigorously at room temperature for 2 hours, separated twice with dichloromethane (300 ml) and distilled water (300 ml), and the organic layers were collected and dehydrated with sodium sulfate. The filtrate was concentrated under reduced pressure.
  • PBr3 phosphorous tribromide, 253.6 ⁇ l, 2.608 mmol, 0.35 eq
  • Diisobutylaluminum hydride 1M solution (DIBAL-H; 1M solution in hexane, 74 ml, 74.0 mmol, 3 eq) was slowly added dropwise to the reaction solution over 30 minutes, and then the reaction temperature was increased to 0 ° C. for 1 hour. Methanol (22 ml) was slowly added dropwise with stirring.
  • reaction solution was transferred to room temperature, stirred for 30 minutes, and a saturated aqueous solution of Rochelle's salt (88 ml) was added thereto.
  • the reaction mixture was stirred vigorously for 2 hours at room temperature, and partitioned twice with dichloromethane (300 ml) and distilled water (300 ml).
  • Trimethylamine (Et3N, 1.04 ml, 7.45 mmol, 1 eq)
  • 4-dimethylaminopyridine (4-dimethylaminopyridine, 4-DMAP, 92 mg, 0.75 mmol, 0.1 eq)
  • di-talt-butyl-dicarbonate (di- tert-butyl-dicarbonate, Boc 2 O, 2.57 ml, 11.18 mmol, 1.5 eq) was added sequentially, and the reaction solution was stirred at room temperature for 2 hours.
  • Lmna G609G / 609G mice were generated through the proper mating of the heterozygous Lmna + / G609G provided by Carlos Lopez-Otin (Universidad de Oviedo, Asturias, Oviedo, Spain).
  • SLC-D011 20 mg / kg mixed with DMOS and PBS was injected intraperitoneally twice a week in 5 week old mice.
  • SLC-D011 dissolved in a concentration of 10 mg / ml in an olein-based solution was orally administered to the mice five times a week, control mice were administered only olein-based solution under the same conditions.
  • Lmna G609G / 609G mice started dosing at 5 weeks of age and were treated with fresh compound solution throughout their lifetime. Lmna + / G609G mice started intraperitoneal treatment at 32 weeks of age.
  • HGPS patients (AG03198, 10-year-old female; AG03199; 10-year-old female), WS patients (AG06300, 37-year-old male; AG03141, 30-year-old female; AG00780, 60-year-old male) and control (GM 00038, 9-year-old female) human fibroblasts obtained from Coriell Cell Repositories (Camden, New Jersey, USA), EMEM medium or antibiotic containing 15% FBS, 2 mM glutamine And maintained in HEMEM containing 26 mM HEPES.
  • HEK293 cell lines were obtained from ATCC and maintained at 37 ° C. using DMEM liquid medium containing 10% FBS and 1% antibiotic.
  • GFP Fluorescence Activated protein
  • GST Glutathione S-transferase
  • Actin 1: 10000; sc-47778; Santa Cruz Biotechnology
  • Lamin A / C 1: 10000; sc-376248; Santa Cruz Biotechnology
  • Progerin Progerin; 1: 300; sc-81611; Santa Cruz Biotechnology
  • Progerin 1: 300; ab66587; Abcam
  • Antibodies such as H3K9me3 (1; 2000; Ab8898; Abcam
  • Lamin A-C Lamin A C-terminal region
  • Progerin C Progerin C
  • the WRN-R1 region (hWRN 424-450) and WRN-R2 region (hWRN 424-476) were produced in a similar manner. Each fragment was loaded into GSH-agarose, washed extensively and eluted using a buffer containing 20 mM reduced glutathione.
  • the eluted fragments were further purified using anion exchange chromatography (HitrapQ) to obtain the WRN-R1 and WRN-R2 amino acid sequences as follows.
  • WRN-R1 HLSPNDNENDTSYVIESDEDELEMEMLK
  • WRN-R2 HLSPNDNENDTSYVIESDEDELEMEMLK HLSPNDNENDTSYVIESDEDELEMEMLK
  • the membrane was incubated with the primary antibody for 1 hour to overnight at 4 ° C. and then reacted for 1 hour at room temperature with the secondary antibody.
  • Peroxidase activity was confirmed by chemiluminescence according to the manufacturer's instructions using the ECL kit (Intron, Seoul, Korea).
  • GST glutathione S-transferase
  • the GST-based fusion lamin AC-terminal region, progerin-C-terminal region, WRN-R1 region or WRN-R2 region was GFP tagged progerin (GFP-Progerin) and lamin A (GFP).
  • GFP-Progerin GFP tagged progerin
  • GFP lamin A
  • anti-lamin A / C, progerin or H3K9Me3 is diluted 1: 200 in blocking buffer to incubate with cells overnight and subsequently anti-goat Ab-FITC or anti-rabbit Ab- Blocking buffer containing rhodamine (1: 500) was incubated for 7 hours and nuclei stained with DAPI. Thereafter, immunofluorescence signals were detected using fluorescence microscopy (Zeiss and Logos).
  • GFP-progerin and GFP-fusion lamin A expression vectors were provided by T. Misteli (National Cancer Institute [NCI], Bethesda, Maryland, USA), and Myc-human WRN vectors and Myc-mouse WRN vectors were purchased from Addgene. .
  • PULSin Polyplus Transfection, New York, USA
  • PULSin reagent 8 ⁇ l was added. The mixture was incubated at room temperature for 15 minutes before cells were added. After 3 hours the serum free medium was replaced with medium containing 10% FBS and incubated for 4 hours. The mixture containing medium was then removed from the wells and filled with fresh medium containing serum.
  • DAPI stained cells were counted in immunofluorescence images.
  • PK pharmacokinetic
  • Hutchinson Gilford's syndrome is a well-known progerin syndrome, a rare genetic disorder. Genetic causes include a single point mutation in Lamin A resulting in abnormal donor conjugation, resulting in progerin with the C-terminal 50 amino acid deleted therein.
  • the inventors of the present invention confirmed that the nuclear malformation of HGPS cells was due to a very strong binding between Lamin A and progerin, and the progerin inhibitor (JH4) from Lamin A binding improved nuclear deformation of HGPS cells. Aging related markers such as, p16 / INK4A, DNA-PK, and H3K9me3 expression were restored. In addition, JH4 treatment via intraperitoneal injection (i.p) prolonged the lifespan of progerin model mice for about 4 weeks.
  • HGPS patients had a very thin blood vessel wall, and intravenous injection was not an appropriate delivery method, confirming the possibility of oral administration of JH4.
  • JH4 JH010 and SLC-D011 compounds exhibited similar activities to JH4, and as shown in FIG. 1D, it was confirmed to exhibit an effect of inhibiting progerin expression.
  • JH010 and SLC-D011 improved the bioavailability (B.A) by 70% and 66%, respectively.
  • SLC-D011 as well as JH4 showed very low water solubility, and since such low water solubility is a problem for compound delivery through oral administration, a suitable solution can be screened to increase the SLC-D011 dissolution rate.
  • Olein-based solutions are also well suited as SLC-D011 carriers because they can increase intestinal absorption without toxicity.
  • SLC-D011 prepared in oral dosage form dissolved in an oleine-based solution was orally administered to Lamn G609G / G609G mice to confirm the in vivo effect. As shown in FIGS. 3C and 3D, the lifespan of Lamn G609G / G609G mice was increased. Extended to 4.5 weeks, weight gain was noted.
  • Olein-based SLC-D011 solution was found to be very useful for HGPS treatment.
  • human and mouse WRN were transfected into HGPS cells and confirmed nuclear morphology and H3K9me3 expression.
  • WRN-R2 was a natural progerin inhibitor.
  • the recombinant WRN-R2 was treated with HGPS cells and WS cells.
  • FIG. was normalized, and H3K9me3 expression was confirmed to be improved.
  • SLC-D011 improved nuclear morphology and cell proliferation similar to HGPS in cells of WS patients, and induced expression of H3K9me3 as in 4G.
  • SLC-D011 can be used to treat Werner's syndrome, which is an adult prematurity.
  • Human skin keratinocytes were incubated with HaCaT cells and normal fibroblasts 9N (GM 00038, 9-year-old female) and N46 (AG13299, 46-year-old male) treated with 2 or 5 ⁇ M SLC-D011 for 24 hours. Afterwards, collagen 1A expression levels were confirmed in HaCaT cells and fibroblasts.
  • SLC-D011 was confirmed to exhibit an effect of increasing the collagen expression in human fibroblasts and keratinocytes.
  • the SLC-D011 compound is suitable as a progerin-lamin A binding inhibitor, and the SLC-D011 compound may be provided for oral administration, so that it may be used as an effective anti-corrosive agent or a composition for improving wrinkles.

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Abstract

La présente invention concerne un nouveau dérivé de décursine, ainsi qu'une composition destinée à la prévention ou au traitement de maladies liées au vieillissement, contenant ledit dérivé en tant que principe actif. Le nouveau dérivé de décursine a présenté un excellent effet d'inhibition de l'expression de la progérine et un excellent effet d'inhibition de la liaison entre la progérine et la lamine A, et il a été confirmé que le nouveau dérivé de décursine prolonge la période de survie de modèles animaux dans lesquels une progéria est induite. Par conséquent, un composé de la présente invention peut être utilisé efficacement dans la prévention ou le traitement de maladies liées au vieillissement telles que la progéria, etc.
PCT/KR2018/004812 2017-04-25 2018-04-25 Composition pharmaceutique destinée à prévenir ou à traiter des maladies liées au vieillissement, contenant un dérivé de décursine comme principe actif Ceased WO2018199633A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US16/605,802 US11008332B2 (en) 2017-04-25 2018-04-25 Pharmaceutical composition for preventing or treating aging-related diseases containing decursin derivative as active ingredient
JP2019558763A JP6826674B2 (ja) 2017-04-25 2018-04-25 デクルシン誘導体を有効成分として含有する老化関連疾患の予防または治療用薬学組成物
CN201880027751.9A CN110573514B (zh) 2017-04-25 2018-04-25 含有紫花前胡素衍生物作为有效成分的老化相关疾病的预防或治疗用药物组合物
EP18791502.0A EP3617211B1 (fr) 2017-04-25 2018-04-25 Composition pharmaceutique destinée à prévenir ou à traiter des maladies liées au vieillissement, contenant un dérivé de décursine comme principe actif

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR20170052787 2017-04-25
KR10-2017-0052787 2017-04-25
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