KR20200039898A - Pharmaceutical composition for preventing or treating aging-related diseases comprising decursin derivatives - Google Patents

Abstract

The present invention relates to a novel decursin derivative and a composition for preventing or treating aging-related diseases containing the same as an active component. The novel decursin derivative exhibits excellent progerin expression inhibitory effect and lamin A binding inhibitory effect. Therefore, a compound of the present invention can be effectively used for preventing or treating aging-related diseases such as progeria etc.

Description

Pharmaceutical composition for preventing or treating aging-related diseases comprising decursin derivatives}

The present invention relates to a novel dekersin derivative and a composition for preventing or treating aging-related diseases containing the same as an active ingredient.

As the lifespan of humans increases, interest in the progress of aging has been actively raised, but there are still many undiscovered areas, and recent studies have mainly focused on genetic or molecular aging mechanisms targeting human premature ejaculation. have.

Premature ejaculation or Hutchinson Gilford progria syndrome (HGPS) is a fatal and rare genetic disorder in which premature aging occurs in young children. In children with premature ejaculation, it appears normal in early childhood but about 9-24 months When this happens, it begins to show a serious delay in growth, and eventually shows a short stature and weight loss. It has a characteristic face shape, systemic atherosclerosis, cardiovascular disease, stroke, hip dislocation, etc., fat layer under the skin is lost, nail defects, joint hardness, and skeleton damage. Patients with premature digestion of heart disease usually die from 8 to 21 years of age due to heart disease and have an average life expectancy of 13 years.

HGPS is a very rare autosomal dominant genetic disease caused by the silent mutation of G608G of Lamin A (LMN A). This mutation creates a new cleavage donor site and produces a selective cleavage site product, Progerin (Prg), which is deleted of 50 amino acids of the C-terminal domain of Lamin A.

The expression of progerin causes morphological changes such as nuclear membrane irregularity or a decrease in nuclear-cytoplasmic lamin A. When inhibition of progerin expression leads to a decrease in nuclear transformation, it has been identified as a major factor in HGPS.

Accordingly, there is a method of relieving progenin by inhibiting farnesylation of progenin as a method of treating premature ejaculation, or removing panesylated lamin A using autophage, but in both cases, side effects There has been no report on the underlying treatment of premature ejaculation.

Korean Patent Publication No. 2012-0106286 (published on September 26, 2012)

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 ejaculation.

The present invention provides a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.

[Formula 1]

The present invention provides a pharmaceutical composition for preventing or treating aging-related diseases containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

In addition, the present invention provides a cosmetic composition for preventing or improving wrinkles comprising a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[Formula 1]

As the novel compound according to the present invention exhibits excellent progerin expression and progerin-lamin A binding inhibitory effect in cells with premature ejaculation, the compound of the present invention is Hutchinson Gilford progria syndrome (HGPS) And it can be effectively used in the treatment of aging-related diseases such as Werner syndrome (werner syndrome), it can also be used as a cosmetic composition for preventing or improving wrinkles as it is found that the compound increases collagen production in skin cells.

1 is a result confirming the effect of inhibiting progerin-lamin A binding,
1A is a result of confirming that aging phenotype inhibition was confirmed in the progestia model mouse in which JH4 was injected intraperitoneally as a result of in vivo PK analysis of JH4, but disappeared very rapidly during PO treatment.
1B is a schematic diagram showing the formation of JH4 derivatives, and is a result of confirming a synthesized JH4 derivative compound by replacing a side chain with an amino bond (JH010) or an ether bond (SLC-D011: D011) to inhibit rapid decomposition in vivo. .
Figure 1C is a result of confirming the effect that the JH4 derivative inhibits Lamin A (Lamin A; LMNA) and progerin interactions, 293 cell lysate transformed with beads bound to GFP-progerin and each compound It is the result of performing the binding inhibition analysis by incubation together.
1D is a result of confirming the effect of inhibiting the expression of JH010 progerin through the analysis of progerin expression, and the result of confirming the effect of inhibiting progerin expression by treating each compound in 293 cells transformed with progerin for 24 hours. 1E is a result of confirming the effect that JH010 improves nuclear morphology and inhibits progerin expression, incubating HGPS cells (AG03198, 10-year-old female; AG03199; 10-year-old female) and compounds for 48 hours. After staining progerin (red), the compounds improved the shape of the abnormal nucleus, and DAPI stands for DNA.
1F is an immunostaining result confirming the effect of inducing H3K9me3 expression by JH010, H3K9me3 inhibition is a very well-known marker in premature ejaculation cells, and immunostaining results show that all compounds effectively result in dbehg H3K9me3 expression in HGPS cells.
Figure 2 shows the results of PK analysis in vivo of JH010.
Figure 3 shows the results of Western blot analysis confirming the expression level of collagen 1A according to the treatment of JH010 in human skin keratinocytes HaCaT cells (A: 6 hours JH010 treatment, B: 12 hours JH010 treatment).

The present invention can provide a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.

[Formula 1]

The present invention can provide a pharmaceutical composition for preventing or treating aging-related diseases containing the compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

The aging-related disease may be premature ejaculation.

More specifically, the premature ejaculation may be selected from the group consisting of Werner syndrome and Hutchinson Gilford syndrome.

The compound represented by Chemical Formula 1 and a pharmaceutically acceptable salt thereof can inhibit the binding between progerin and lamin A.

In one embodiment of the present invention, the pharmaceutical composition is any one selected from the group consisting of injections, granules, powders, tablets, pills, capsules, suppositories, gels, suspensions, emulsions, drops or liquids according to conventional methods. Can be used.

In another embodiment of the present invention, the pharmaceutical composition is a suitable carrier, excipient, disintegrant, sweetener, coating agent, swelling agent, lubricant, lubricant, flavoring agent, antioxidant, buffer, bacteriostatic agent, commonly used in the manufacture of a pharmaceutical composition, It may further include one or more additives selected from the group consisting of diluents, dispersants, surfactants, binders and lubricants.

Specifically, 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 dosage forms for oral administration include tablets, pills, powders, granules and capsules. Agents, and the like, and these solid preparations may be prepared by mixing at least one excipient in the composition, for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like. In addition, lubricants such as magnesium stearate and talc may be used in addition to simple excipients. Liquid preparations for oral use include suspending agents, intravenous solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, may be included. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin butter, and glycerogelatin may be used.

According to an embodiment of the present invention, the pharmaceutical composition is intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, intrasternal, transdermal, intranasal, inhalation, topical, rectal, oral, intraocular or intradermal. Routes can be administered to a 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 and duration of administration, and may be appropriately selected by those skilled in the art. According to one embodiment of the present invention is not limited thereto, the daily dosage may be 0.01 to 200 mg / kg, specifically 0.1 to 200 mg / kg, and more specifically 0.1 to 100 mg / kg. The administration may be administered once a day or divided into several times, and the scope of the present invention is not limited thereby.

In the present invention, the 'subject' may be a mammal, including a human, but is not limited to these examples.

In addition, the present invention can provide a cosmetic composition for preventing or improving wrinkles comprising a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[Formula 1]

The compound represented by Formula 1 and a pharmaceutically acceptable salt thereof may improve collagen production in keratinocytes and fibroblasts.

The cosmetic composition may include a stabilizing agent, a solubilizing agent, a common auxiliary agent such as vitamins, pigments and fragrances, and a carrier in addition to the compound represented by Chemical 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 can be prepared in the form of a sun cream, soft lotion, converging lotion, nutrition lotion, nutrition cream, massage cream, essence, eye cream, pack, spray or powder.

When 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. .

When the formulation is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder may be used as a carrier component. In particular, in the case of a spray, additionally chlorofluorohydrocarbon, propane / butane Or propellants such as dimethyl ether.

When the formulation is a solution or emulsion, a solvent, solubilizer or emulsifier is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -Fatty acid esters of butyl glycol oil, glycerol aliphatic esters, polyethylene glycol or sorbitan.

When the formulation is a suspension, liquid diluents such as water, ethanol or propylene glycol as carrier components, ethoxylated isostearyl alcohol, suspensions such as polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters, microcrystalline cellulose , Aluminum metahydroxide, bentonite, agar or trakant, and the like.

Hereinafter, examples will be described in detail to help understanding of the present invention. However, the following examples are merely illustrative of the contents of the present invention, and the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

< Reference example > Materials and equipment

¹ H and ¹³ C NMR spectra were measured using a JNM-AL 400 spectrometer (400 MHz, JEOL, Japan), and the melting point was measured for mass spectrometry in an Electrotheramal melting point apparatus (Yamaco.MD-S3). The instrument was performed using an API 2000 LC / MS / MS spectrometer (PE Sciex, Canada), respectively.

In addition, the optical rotations were measured on a JASCO DIP-360 automatic digital polarimeter, and the purity of chiral materials was measured by HPLC (Shimadzu LC-6AD, Japan), column (CHIRACEL OD-H 0.46 cmф x 25 cm, DAICEL CHEMICAL IND., Co. Osaka, Japan).

Silica gel for material separation was used as SiliaFlash® P60 (SILICYCLE, 230 ~ 400 mesh), and TLC silica gel 60 F254 (MERCK) product was used as the thin film TLC plate.

The solvents and reagents used for the synthesis of the materials were purchased from Sigma-Aldrich, Fluka, TCI, Junsei, Duksan pure chemical, SK Chemical and SAMCHUN chemical, and used.

< Example  1> Carbamate-form (+)- Deckersin ( decursin ) Synthesis of derivatives [(7S)-(+)-(E) -2- (Pyridin-3-yl) ethenyl carbamic acid, 8,8-dimethyl-2-oxo-6,7-dihydro- 2H, 8H -pyrano [3,2- g ] chromen-7-yl-ester; JH010]

JH010 was synthesized in the same manner as in Scheme 1 below.

1. Synthesis process Ⅰ

[Scheme 1]

a. dry benzene, TEA, DPPA, 3hr; b. dry benzene, reflux, 5 hr; c. TEA, 4-DMAP, 100 ℃, 3hr, 53%

After dissolving trans-3- (3-pyridyl) acrylic acid (Compound 1, 1.5eq) in dry benzene in a round flask, triethylamine (TEA, 1.5eq), diphenyl phosphoryl azide (DPPA, 1.5eq) Was added and reacted at 80 ° C for 3 hours. After extracting with water and ethyl acetate (EA), and then removing water with sodium sulfate, the crude product concentrated under reduced pressure was dissolved in dry benzene again and heated to reflux at 80 ° C for a day. To this, (+)-deckersinol (Compound 4, 1eq) was added, triethylamine (TEA, 1.2eq), and 4- (dimethylamino) pyridine (DMAP, 0.4eq) were added and reacted at 100 ° C for 3 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column separation using hexane and ethyl acetate as mobile phases to obtain JH010.

+138.5667 (c=3, CHCl₃); ¹H NMR(400MHz, DMSO-d6): 10.038(d, J=10.4Hz, NH), 8.446(s, 1H), 8.301(dd, J=1.2, 4.8Hz, 1H), 7.923(d, J=9.6Hz, 1H), 7.756(d, J=7.6Hz, 1H), 7.498(s, 1H), 7.250(m, 2H), 6.809(s, 1H), 6.268(d, J=9.6Hz, 1H), 6.009(d, J=14.8Hz, 1H), 5.069(t, J=3.6Hz, 1H), 3.265(dd, J=4.4, 18.0Hz, 1H), 2.928(dd, J=3.2, 17.6Hz, 1H), 1.393(s, CH3), 1.323(s, CH3); IT-TOF/MS 415.1281[M+Na]⁺.Yield = 53.0%; ivory-white solid, mp: 125.9 ° C, Rf = 0.12 (n-HX: EA = 1: 2);

+138.5667 (c = 3, CHCl ₃ ); ¹ H NMR (400 MHz, DMSO-d6): 10.038 (d, J = 10.4 Hz, NH), 8.446 (s, 1H), 8.301 (dd, J = 1.2, 4.8 Hz, 1H), 7.923 (d, J = 9.6Hz, 1H), 7.756 (d, J = 7.6Hz, 1H), 7.498 (s, 1H), 7.250 (m, 2H), 6.809 (s, 1H), 6.268 (d, J = 9.6Hz, 1H) , 6.009 (d, J = 14.8Hz, 1H), 5.069 (t, J = 3.6Hz, 1H), 3.265 (dd, J = 4.4, 18.0Hz, 1H), 2.928 (dd, J = 3.2, 17.6Hz, 1H), 1.393 (s, CH3), 1.323 (s, CH3); IT-TOF / MS 415.1281 [M + Na] ⁺ .

< Example  2> Lamin  A ( LMN  A)- Progestin  Confirming the effect of JH010 as a binding inhibitor

1. Animal Experiment

Animal experiments were conducted by accreditation assessment associations and laboratory animal care accreditation bodies, in accordance with animal policies approved by Pusan National University.

Lmna ^{G609G / 609G} mice were generated through appropriate mating of heterozygous Lmna ^{+ / G609G} provided by Carlos Lopez-Otin (Universidad de Oviedo, Asturias, Oviedo, Spain).

20 mg / kg of JH010 or SLC-D011 mixed with DMOS and PBS was injected intraperitoneally twice a week into 5 week old mice. In addition, JH010 or SLC-D011 dissolved in an olein-based solution at a concentration of 10 mg / ml was orally administered to mice 5 times a week, and the control mice were administered only an olein-based solution under the same conditions as above.

Lmna ^{G609G / 609G} mice began administration at 5 weeks of age and treated with fresh compound solutions throughout their lifetime. Lmna ^{+ / G609G} mice started intraperitoneal treatment at 32 weeks of age.

2. Cell culture and reagents

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 were obtained from Coriell Cell Repositories (Camden, New Jersey, USA), 15% FBS, EMEM medium containing 2 mM glutamine or antibiotic In HEMEM with 26 mM HEPES.

The HEK293 cell line was obtained from ATCC and maintained at 37 ° C. using DMEM liquid medium containing 10% FBS and 1% antibiotic.

3. Antibodies and reagents

GFP (Full name; 1: 1000; sc-9996; Santa Cruz Biotechnology); Glutathione S-transferase (Glutathione S-transferase; GST; 1: 5000; sc-138; Santa Cruz Biotechnology); Actin (Actin; 1: 10000; sc-47778; Santa Cruz Biotechnology); Lamin A / C (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) were used in the experiment.

4. Recombinant protein

To produce a recombinant protein, 100 AA was cloned from the upstream of the termination codon via PCR to produce a recombinant lamin A C-terminal region (Lamin A-C) and a progerin C-terminal region (Progerin C).

The WRN-R1 region (hWRN 424-450) and WRN-R2 region (hWRN 424-476) were produced in a similar manner. After loading each fragment to GSH-agarose, it was washed extensively and eluted with a buffer containing 20 mM reduced glutathione.

The eluted fragments were further purified using anion exchange chromatography (HitrapQ) to obtain the following WRN-R1 and WRN-R2 amino acid sequences.

WRN-R1: HLSPNDNENDTSYVIESDEDELEMEMLK

WRN-R2: HLSPNDNENDTSYVIESDEDELEMEMLK HLSPNDNENDTSYVIESDEDELEMEMLK

5. Western Blot  analysis

Whole cell lysates were prepared using RIPA.

15 μg cell extract was isolated on SDS-PAGE and transferred onto PVDF membrane.

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 using the secondary antibody.

Peroxidase activity was confirmed by chemiluminescence according to the manufacturer's instructions using the ECL kit (Intron, Seoul, Korea).

6. Protein-protein interaction analysis

To analyze protein-protein interactions, glutathione S-transferase (GST) immune pull-down analysis was performed.

To detect the interaction, GST-based fused lamin AC-terminal region, progerin-C-terminal region, WRN-R1 region or WRN-R2 region are GFP-tagged progerin (GFP-Progerin) and lamin A (GFP) HEK293 cell lysate transfected with -Lamin A) was incubated at room temperature for 30 minutes.

Then, washed once with PBS, the precipitated material was collected and separated on SDS-PAGE, followed by western blot with anti-GFP and GST.

In order to confirm the competitive response of WRN-R1 and R2 to prominin and lamin A binding, GFP-ramine A was used for GST-progerin-coupled beads in the presence or absence of WRN-R1 or R2 recombinant protein. Incubated with overexpressed 293 lysate.

7. Immunofluorescence  Staining and aging specific acid β-galactosidase activity staining

Cells were inoculated onto the cover glass and appropriate vectors were transfected.

After fixing for 1 hour at 4 ° C using 100% methanol or 1% paraformaldehyde (PFA), the cells were incubated with a blocking buffer (PBS + anti-human-Ab; 1: 400).

After washing twice with PBS, anti-lamin A / C, progerin or H3K9Me3 was diluted 1: 200 in blocking buffer overnight, incubated with cells overnight and subsequently anti-goat Ab-FITC or anti-rabbit Ab- Blocking buffer (1: 500) containing rhodamine (rhodamin) was incubated for 7 hours, and nuclei were stained with DAPI. Thereafter, immunofluorescence signals were detected using fluorescence microscopy (Zeiss and Logos).

For aging specific acid-β-galactosidase activity staining, cells were washed once with PBS (pH 7.2) and fixed with PBS containing 0.5% glutaraldehyde.

Then washed with PBS and cells were stained overnight with X-gal solution at 37 ° C.

8. plasma  Transfection and protein transport

GFP-progerin and GFP-fusion lamin A expression vectors were provided by T. Misteli (National Cancer Institute [NCI], Bethesda, Maryland, USA), Myc-human WRN vector and Myc-mouse WRN vector were purchased from Addgene. .

Transfection was performed according to the manufacturer's instructions using jetPEI (Polyplus Transfection) and PULSin (Polyplus Transfection, New York, USA).

To deliver WRN-R1 and R2 proteins into HGPS cells, PULSin (Polyplus Transfection, New York, USA) was used according to the manufacturer's instructions.

After diluting the recombinant protein (2 μg) with 200 μl of 20 mM Hepes, PULSin reagent (8 μl) was added. Cells were added after the mixture was incubated for 15 minutes at room temperature. After 3 hours, the serum-free medium was replaced with a medium containing 10% FBS and incubated for 4 hours. The medium-containing mixture was then removed from the wells and fresh medium containing serum was filled.

9. Cell count

To count cells with malformed nuclei, acquired immunofluorescence images were used. Nuclear membranes that appeared to be malformed dependent on Lamin A staining were counted in randomly selected areas and the counted cells were expressed as a percentage.

To measure cell proliferation, DAPI stained cells were counted in immunofluorescence images.

10. Compound pharmacokinetics pharmacokinetic ; PK) analysis and in vitro ADME  Confirm

For pharmacokinetic (PK) analysis, 10% DMSO, 5% Tween 90 and 95% physiological saline solution in which JH4 was dissolved at 5 mg / kg was injected intraperitoneally, and 10% NMP and 90% PEG400 solution in which JH4 was dissolved at 10 mg / kg was added. It was administered orally. The blood concentration of JH4 was analyzed by LC-MS / MS every predetermined time, and other compounds were also PK analyzed in the same process.

In vitro ADME studies (plasma protein binding, CYP inhibition, microsomal stability, plasma stability and hERG inhibition) were performed in a new drug development center by standard methods.

11. Progestin - Lamin  Confirming the effect of JH010 as A binding inhibitor

Hutchinson Gilford syndrome is a well-known progerin syndrome, a very rare genetic disorder. As a genetic cause, a single point mutation in lamin A occurs, resulting in abnormal donor junction, and thus, 50 amino acids in the C-terminal end are deleted to produce progerin.

In the previous report, 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 progerin inhibitor (JH4) from lamin A binding improved nuclear transformation of HGPS cells. , aging related markers such as p16 / INK4A, DNA-PK, and H3K9me3 expression were recovered. In addition, JH4 treatment via intraperitoneal injection (i.p) prolonged the lifespan of progestin model mice for about 4 weeks.

However, considering the patient's condition, the HGPS patient has a very thin blood vessel wall, so intravenous injection is not an appropriate delivery method, so we confirmed the possibility of oral administration of JH4.

As a result, the intravenous injection and oral administration of JH4 as shown in FIG. 1A, Table 1 and Table 2 showed a very short half-life in vivo, and thus, in vivo availability (B.A) could not be confirmed.

Accordingly, in order to obtain a stable compound in vivo, various compounds were modified from JH4, and GST-immune sedimentation analysis and progerin expression analysis were performed to confirm 41 other types of JH4 derivatives. As shown in 1C, the JH010 compound exhibited activity similar to JH4, and was confirmed to exhibit an effect of inhibiting progerin expression as shown in FIG.

In addition, referring to FIGS. 1E and 1F, the JH010 compound induced H3K9me3 expression and improved the nuclear malformation of HGPS cells.

In the PK analysis result, as shown in FIG. 2A, JH010 compound improved bioavailability (B.A) by 70%.

< Example  3> Confirm the effect of JH010 compound on skin aging improvement

As the previous experiment confirmed that the JH010 compound has a therapeutic effect on aging-related diseases, the effect of JH010 on the human skin keratinocytes HaCaT cells was confirmed.

Human skin keratinocytes were treated with 2 μM or 5 μM JH010 for HaCaT cells, followed by incubation for 6 or 24 hours, and then the expression level of collagen 1A in HaCaT cells was confirmed.

As a result, it was confirmed that the JH010 compound shows an effect of increasing collagen expression in human keratinocytes as shown in FIGS. 3A and 3B.

From the above results, the JH010 compound was found to be suitable as a progerin-lamin A binding inhibitor, and the JH010 compound can be provided for oral administration, and thus can be used as an effective agent for treating premature aging or a wrinkle improving composition.

Since the specific parts of the present invention have been described in detail above, it is obvious to those skilled in the art that this specific technique is only a preferred embodiment, whereby the scope of the present invention is not limited. something to do. Therefore, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (7)

A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

A pharmaceutical composition for the prevention or treatment of aging-related diseases, including a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

The method according to claim 2, wherein the aging-related disease is a pharmaceutical composition for preventing or treating aging-related diseases, characterized in that the premature ejaculation. The pharmaceutical composition for preventing or treating aging-related diseases according to claim 3, wherein the premature ejaculation is selected from the group consisting of Werner syndrome and Hutchinson Gilford progria syndrome. The method according to claim 2, wherein the compound represented by Formula 1 and a pharmaceutically acceptable salt thereof is a pharmaceutical composition for the prevention or treatment of aging-related diseases, characterized in that to inhibit the binding between progerin and lamin A. A cosmetic composition for preventing or improving wrinkles comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

The method of claim 6, wherein the compound represented by Formula 1 and a pharmaceutically acceptable salt thereof is a cosmetic composition for preventing or improving wrinkles, characterized in that to enhance collagen production in keratinocytes and fibroblasts.

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