WO2023075361A1 - Pharmaceutical composition for preventing or treating atherosclerosis comprising xanthine derivative as active ingredient - Google Patents
Pharmaceutical composition for preventing or treating atherosclerosis comprising xanthine derivative as active ingredient Download PDFInfo
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- WO2023075361A1 WO2023075361A1 PCT/KR2022/016344 KR2022016344W WO2023075361A1 WO 2023075361 A1 WO2023075361 A1 WO 2023075361A1 KR 2022016344 W KR2022016344 W KR 2022016344W WO 2023075361 A1 WO2023075361 A1 WO 2023075361A1
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A23V2250/00—Food ingredients
- A23V2250/30—Other Organic compounds
Definitions
- the pharmaceutical composition is characterized by reducing the proliferation of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor (PDGF).
- VSMCs vascular smooth muscle cells
- PDGF platelet-derived growth factor
- composition for preventing or treating atherosclerosis and the composition for health functional food containing the xanthine derivative as an active ingredient are equally applicable unless contradictory.
- the present invention provides a pharmaceutical composition for preventing or treating atherosclerosis comprising a xanthine derivative represented by the following [Formula 1] as an active ingredient.
- the pharmaceutical composition of the present invention may be prepared using pharmaceutically suitable and physiologically acceptable adjuvants in addition to the above active ingredients, or may be administered to mammals.
- adjuvant excipients, disintegrants, sweeteners, binders, coating agents, expanding agents, lubricants, lubricants, or flavoring agents may be used.
- pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level depends on the type, severity, activity of the drug, and drug sensitivity, time of administration, route of administration and excretion rate, duration of treatment, factors including drugs used concurrently, and other factors well known in the medical field.
- the pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art.
- the present invention also provides a use of a xanthine derivative represented by the following [Formula 1] as a therapeutic agent for atherosclerosis.
- RNA Total RNA (0.5 ⁇ g) from transfected hVSMC was extracted using the TRIzol reagent kit (Invitrogen) according to the manufacturer's protocol, and RNA integrity was assessed using TapStation RNA screen tape. After total RNA extraction, an RNA library was independently prepared using the Illumina TruSeq Stranded Total RNA Library Prep Gold Kit (Illumina, Inc., San Diego, CA, USA). The digested RNA fragments were copied into first-strand cDNA using SuperScript II reverse transcriptase (Invitrogen, Carlsbad, CA, USA) using random primers (Invitrogen). Qualified cDNA libraries were sequenced on the Illumina NovaSeq platform (Illumina, Inc., San Diego, CA, USA).
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Abstract
The present invention relates to a pharmaceutical composition for preventing or treating atherosclerosis comprising a xanthine derivative as an active ingredient and, more particularly, to a pharmaceutical composition for preventing or treating atherosclerosis by inhibiting the proliferation of vascular smooth muscle cells (VSMCs) induced by a platelet derived growth factor (PDGF).
Description
본 발명은 크산틴 유도체를 유효성분으로 포함하는 죽상동맥경화증 예방 또는 치료용 약학적 조성물에 관한 것으로, 보다 구체적으로 혈소판 유래 성장 인자(Platelet Derived Growth Factor, PDGF)로 유도된 혈관 평활근 세포(Vascular Smooth Muscle Cells, VSMCs)의 증식을 억제시킴으로써 죽상동맥경화증을 예방 또는 치료할 수 있는 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating atherosclerosis comprising a xanthine derivative as an active ingredient, and more specifically, to a vascular smooth muscle cell induced by platelet-derived growth factor (PDGF) It relates to a pharmaceutical composition capable of preventing or treating atherosclerosis by inhibiting the proliferation of muscle cells (VSMCs).
죽상동맥경화증은 죽상동맥경화성 플라크(atherosclerotic plaques)를 형성하는 복잡한 염증 반응 과정에 의한 지방-부유 대식세포(거품 세포)의 축적과, 섬유질 및 평활근 세포의 증식으로 인해 동맥벽이 두꺼워진 CVD 환자들이 가진 주요 질환으로, 세계적으로 높은 사망률을 가지는 질환으로 알려져 있으며, 국내에서도 사망원인 2~3위를 차지할 정도로 위험한 질환이다. 노화 과정에서의 염증성 사이토카인 수준 상승은 혈관을 손상시키고 죽상동맥경화증을 악화시키는데 중요한 역할을 한다.Atherosclerosis is a disease of CVD patients with thickened arterial walls due to the accumulation of fat-rich macrophages (foam cells) and the proliferation of fibrous and smooth muscle cells by a complex inflammatory process that forms atherosclerotic plaques. As a major disease, it is known as a disease with a high mortality rate worldwide, and it is a dangerous disease that ranks as the second or third leading cause of death in Korea. Elevated levels of inflammatory cytokines during the aging process play an important role in damaging blood vessels and exacerbating atherosclerosis.
에제티미브는, 콜레스테롤 흡수에 중요한 역할을 하는 창자 브러쉬 보더 막(intestinal brush border membrane) 상의 단백질인 니만-피크 C1-유사 1(Niemann-Pick C1-like 1: NPC1L1)의 작용을 억제한다. 담즙산 금속 이온 봉쇄제(bile acid sequestrant)는 콜레스테롤 흡수뿐만 아니라 담즙산 재흡수를 억제한다. 반면, 고-밀도 리포단백질(HDL) 콜레스테롤 수준은 질환 위험과 역으로 상관관계가 있으며, HDL은 콜레스테롤 역수송을 매개하고, 항산화 활성을 나타낸다. HDL 콜레스테롤 수준을 향상시키거나 HDL 기능을 개선하기 위한 약물 요법이 탐구되었으나, 아직까지 제한된 성공만을 거두었다 (Shih et al., 2013).Ezetimibe inhibits the action of Niemann-Pick C1-like 1 (NPC1L1), a protein on the intestinal brush border membrane that plays an important role in cholesterol absorption. Bile acid sequestrants inhibit cholesterol absorption as well as bile acid reabsorption. On the other hand, high-density lipoprotein (HDL) cholesterol levels are inversely correlated with disease risk, and HDL mediates reverse cholesterol transport and exhibits antioxidant activity. Drug therapies to improve HDL cholesterol levels or improve HDL function have been explored, but with limited success so far (Shih et al., 2013).
죽상동맥경화증은 다양한 치료 옵션의 유효성에도 불구하고, 죽상동맥경화증의 치료에 관한 주요한 미충족된 의학적 요구가 존재한다. 특히, 진행성 증상의 죽상동맥경화증을 앓는 환자에서 기존 플라크 부담(plaque burden)의 감소가 미해결된 이슈이다.BACKGROUND OF THE INVENTION Despite the effectiveness of various treatment options for atherosclerosis, a major unmet medical need exists for the treatment of atherosclerosis. In particular, reduction of pre-existing plaque burden in patients with progressive symptomatic atherosclerosis is an unresolved issue.
따라서, 전술한 문제점을 보완하기 위해 본 발명가들은 죽상동맥경화증을 효과적으로 치료하고 예방할 수 있는 물질의 개발이 시급하다 인식하여, 본 발명을 완성하였다.Therefore, in order to overcome the above problems, the inventors of the present invention recognized the urgent need to develop a substance capable of effectively treating and preventing atherosclerosis, and completed the present invention.
본 발명의 목적은 혈소판 유래 성장 인자(Platelet Derived Growth Factor, PDGF)로 유도된 혈관 평활근 세포(Vascular Smooth Muscle Cells, VSMCs)의 증식을 억제시킴으로써 죽상동맥경화증을 예방 또는 치료할 수 있는 약학적 조성물 및 건강기능식품용 조성물을 제공하는 것이다.An object of the present invention is to provide a pharmaceutical composition and health that can prevent or treat atherosclerosis by inhibiting the proliferation of Vascular Smooth Muscle Cells (VSMCs) induced by Platelet Derived Growth Factor (PDGF). It is to provide a composition for functional food.
발명이 이루고자 하는 기술적 과제들은 이상에서 언급한 기술적 과제들로 제한되지 않으며, 언급되지 않은 또 다른 기술적 과제들은 본 발명의 기재로부터 당해 분야에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있다.The technical problems to be achieved by the present invention are not limited to the technical problems mentioned above, and other technical problems not mentioned can be clearly understood by those skilled in the art from the description of the present invention.
상기 목적을 달성하기 위하여, 본 발명은 크산틴 유도체를 유효성분으로 포함하는 죽상동맥경화증 예방 또는 치료용 약학적 조성물 및 건강기능식품용 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating atherosclerosis and a composition for health functional food containing a xanthine derivative as an active ingredient.
이하, 본 명세서에 대하여 더욱 상세하게 설명한다.Hereinafter, this specification will be described in more detail.
본 발명은 하기 [화학식 1]로 표시되는 크산틴 유도체를 유효성분으로 포함하는 것을 특징으로 하는 죽상동맥경화증 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating atherosclerosis, which comprises as an active ingredient a xanthine derivative represented by the following [Formula 1].
[화학식 1][Formula 1]
상기 [화학식 1]에서 상기 X는 F, Cl 또는 Br이다.In [Formula 1], X is F, Cl or Br.
본 발명에 있어서, 상기 약학적 조성물은 상기 약학적 조성물 총 중량% 대비 상기 [화학식 1]로 표시되는 크산틴 유도체를 0.01 중량% 내지 99.9 중량%로 포함하는 것을 특징으로 한다.In the present invention, the pharmaceutical composition is characterized in that it comprises 0.01% by weight to 99.9% by weight of the xanthine derivative represented by the [Formula 1] relative to the total weight% of the pharmaceutical composition.
본 발명에 있어서, 상기 약학적 조성물은 혈소판 유래 성장 인자(Platelet Derived Growth Factor, PDGF)로 유도된 혈관 평활근 세포(Vascular Smooth Muscle Cells, VSMCs)의 증식을 감소시키는 것을 특징으로 한다.In the present invention, the pharmaceutical composition is characterized by reducing the proliferation of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor (PDGF).
본 발명에 있어서, 상기 약학적 조성물은 PCK2의 증식을 감소시키는 것을 특징으로 한다.In the present invention, the pharmaceutical composition is characterized by reducing the proliferation of PCK2.
또한, 본 발명은 하기 [화학식 1]로 표시되는 크산틴 유도체를 유효성분으로 포함하는 것을 특징으로 하는 죽상동맥경화증 예방 또는 개선용 건강기능식품용 조성물을 제공한다.In addition, the present invention provides a health functional food composition for preventing or improving atherosclerosis, characterized in that it comprises a xanthine derivative represented by the following [Formula 1] as an active ingredient.
[화학식 1][Formula 1]
상기 [화학식 1]에서 상기 X는 F, Cl 또는 Br이다.In [Formula 1], X is F, Cl or Br.
본 발명에 있어서, 상기 건강기능식품용 조성물은 상기 건강기능식품용 조성물을 함유하는 건강기능식품 총 중량% 대비 상기 [화학식 1]로 표시되는 크산틴 유도체를 0.01 중량% 내지 99.9 중량%로 포함하는 것을 특징으로 한다.In the present invention, the composition for health functional food comprises 0.01% to 99.9% by weight of the xanthine derivative represented by the [Formula 1] relative to the total weight% of health functional food containing the composition for health functional food characterized by
상기 크산틴 유도체를 유효성분으로 포함하는 죽상동맥경화증 예방 또는 치료용 약학적 조성물 및 건강기능식품용 조성물에 언급된 모든 사항은 모순되지 않는 한 동일하게 적용된다.All matters mentioned in the pharmaceutical composition for preventing or treating atherosclerosis and the composition for health functional food containing the xanthine derivative as an active ingredient are equally applicable unless contradictory.
본 발명의 약학적 조성물 및 건강기능식품은 혈소판 유래 성장 인자(Platelet Derived Growth Factor, PDGF)로 유도된 혈관 평활근 세포(Vascular Smooth Muscle Cells, VSMCs)의 증식을 억제시킴으로써 죽상동맥경화증을 예방 또는 치료할 수 있다.The pharmaceutical composition and health functional food of the present invention can prevent or treat atherosclerosis by inhibiting the proliferation of Vascular Smooth Muscle Cells (VSMCs) induced by Platelet Derived Growth Factor (PDGF). there is.
본 발명의 효과들은 이상에서 언급한 효과들로 제한되지 않으며, 언급되지 않은 또 다른 효과들은 청구범위의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.The effects of the present invention are not limited to the effects mentioned above, and other effects not mentioned will be clearly understood by those skilled in the art from the description of the claims.
도 1은 PCK2의 발현과 손상된 혈관에서 신생내막 증식 사이의 관련성 확인한 이미지이다.1 is an image confirming the relationship between the expression of PCK2 and neointimal proliferation in damaged blood vessels.
도 2는 혈소판 유래 성장 인자와 혈관 평활근 세포 상관관계를 확인한 그래프이다.2 is a graph confirming the correlation between platelet-derived growth factor and vascular smooth muscle cells.
도 3은 본 발명에 따른 [화학식 1]로 표시되는 크산티 유도체의 인간 혈관 평활근 세포(human VSMCs, hVSMC) 증식 억제 확인한 그래프이다.Figure 3 is a graph confirming the inhibition of human vascular smooth muscle cell (human VSMCs, hVSMC) proliferation by the xanthi derivative represented by [Formula 1] according to the present invention.
본 명세서에서 사용되는 용어는 본 발명에서의 기능을 고려하면서 가능한 현재 널리 사용되는 일반적인 용어들을 선택하였으나, 이는 당 분야에 종사하는 기술자의 의도 또는 판례, 새로운 기술의 출현 등에 따라 달라질 수 있다. 또한, 특정한 경우는 출원인이 임의로 선정한 용어도 있으며, 이 경우 해당되는 발명의 설명 부분에서 상세히 그 의미를 기재할 것이다. 따라서 본 발명에서 사용되는 용어는 단순한 용어의 명칭이 아닌, 그 용어가 가지는 의미와 본 발명의 전반에 걸친 내용을 토대로 정의되어야 한다.The terms used in this specification have been selected from general terms that are currently widely used as much as possible while considering the functions in the present invention, but these may vary depending on the intention of a person skilled in the art, precedent, or the emergence of new technologies. In addition, in a specific case, there is also a term arbitrarily selected by the applicant, and in this case, the meaning will be described in detail in the description of the invention. Therefore, the term used in the present invention should be defined based on the meaning of the term and the overall content of the present invention, not simply the name of the term.
다르게 정의되지 않는 한, 기술적이거나 과학적인 용어를 포함해서 여기서 사용되는 모든 용어들은 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 것과 동일한 의미를 가지고 있다. 일반적으로 사용되는 사전에 정의되어 있는 것과 같은 용어들은 관련 기술의 문맥상 가지는 의미와 일치하는 의미를 가지는 것으로 해석되어야 하며, 본 출원에서 명백하게 정의하지 않는 한, 이상적이거나 과도하게 형식적인 의미로 해석되지 않는다.Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related art, and unless explicitly defined in this application, it should not be interpreted in an ideal or excessively formal meaning. don't
수치 범위는 상기 범위에 정의된 수치를 포함한다. 본 명세서에 걸쳐 주어진 모든 최대의 수치 제한은 낮은 수치 제한이 명확히 쓰여져 있는 것처럼 모든 더 낮은 수치 제한을 포함한다. 본 명세서에 걸쳐 주어진 모든 최소의 수치 제한은 더 높은 수치 제한이 명확히 쓰여져 있는 것처럼 모든 더 높은 수치 제한을 포함한다. 본 명세서에 걸쳐 주어진 모든 수치 제한은 더 좁은 수치 제한이 명확히 쓰여져 있는 것처럼, 더 넓은 수치 범위 내의 더 좋은 모든 수치 범위를 포함할 것이다.Numerical ranges are inclusive of the values defined therein. Every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written. Every minimum numerical limitation given throughout this specification includes every higher numerical limitation, as if such higher numerical limitations were expressly written. Every numerical limitation given throughout this specification will include every better numerical range within the broader numerical range, as if the narrower numerical limitations were expressly written.
이하, 본 발명의 실시예를 상세히 기술하나, 하기 실시예에 의해 본 발명이 한정되지 아니함은 자명하다.Hereinafter, embodiments of the present invention will be described in detail, but it is obvious that the present invention is not limited by the following examples.
약학적 조성물pharmaceutical composition
본 발명은 하기 [화학식 1]로 표시되는 크산틴 유도체를 유효성분으로 포함하는 죽상동맥경화증 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating atherosclerosis comprising a xanthine derivative represented by the following [Formula 1] as an active ingredient.
[화학식 1][Formula 1]
상기 [화학식 1]에서 상기 X는 F, Cl 또는 Br이다.In [Formula 1], X is F, Cl or Br.
상기 약학적 조성물은 상기 약학적 조성물 총 중량% 대비 상기 [화학식 1]로 표시되는 크산틴 유도체를 0.01 중량% 내지 99.9 중량%로 포함할 수 있으며, 바람직하게는 0.1 중량% 내지 99 중량%일 수 있으나, 이에 한정되지 않는다.The pharmaceutical composition may include 0.01% to 99.9% by weight of the xanthine derivative represented by [Formula 1], preferably 0.1% to 99% by weight, based on the total weight% of the pharmaceutical composition. However, it is not limited thereto.
본 발명의 약학적 조성물은 상기 유효 성분 이외에 약제학적으로 적합하고 생리학적으로 허용되는 보조제를 사용하여 제조되거나, 포유동물에게 투여될 수 있다. 상기 보조제로는 부형제, 붕해제, 감미제, 결합제, 피복제, 팽창제, 윤활제, 활택제 또는 향미제 등을 사용할 수 있다.The pharmaceutical composition of the present invention may be prepared using pharmaceutically suitable and physiologically acceptable adjuvants in addition to the above active ingredients, or may be administered to mammals. As the adjuvant, excipients, disintegrants, sweeteners, binders, coating agents, expanding agents, lubricants, lubricants, or flavoring agents may be used.
또한, 본 발명의 약학적 조성물은 투여를 위해서 상기 기재한 약학적으로 유효한 양의 유효 성분 이외에 추가로 약제학적으로 허용 가능한 담체를 1종 이상 포함하여 약제학적 조성물로 바람직하게 제제화할 수 있다.In addition, the pharmaceutical composition of the present invention may be preferably formulated as a pharmaceutical composition by including one or more pharmaceutically acceptable carriers in addition to the above-described pharmaceutically effective amount of the active ingredient for administration.
상기에서 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명에 다른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.In the above, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level depends on the type, severity, activity of the drug, and drug sensitivity, time of administration, route of administration and excretion rate, duration of treatment, factors including drugs used concurrently, and other factors well known in the medical field. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art.
구체적으로 본 발명의 약학적 조성물의 유효량은 환자의 연령, 성별, 상태, 체중, 체내에 활성 성분의 흡수도, 불활성율 및 배설속도, 질병종류, 병용되는 약물에 따라 달라질 수 있으며, 일반적으로는 체중 1 kg 당 0.001 내지 1000 mg, 바람직하게는 200 mg 내지 600 mg을 매일 투여하거나, 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나 투여 경로, 비만의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, body weight, absorption rate, inactivation rate and excretion rate of the active ingredient in the body, type of disease, and concomitant drugs, generally 0.001 to 1000 mg, preferably 200 mg to 600 mg per 1 kg of body weight may be administered daily or divided into 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, severity of obesity, gender, weight, age, etc., the dosage is not limited to the scope of the present invention in any way.
또한, 상기에서 "약제학적으로 허용되는"이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 조성물을 말한다. 상기 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다.In addition, "pharmaceutically acceptable" as used herein refers to a composition that is physiologically acceptable and does not cause allergic reactions such as gastrointestinal disorders and dizziness or similar reactions when administered to humans. Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In addition, fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers and preservatives may be further included.
또한, 본 발명의 조성물은 인간을 포함하는 죽상동맥경화증 치료를 필요로하는 개체에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당업계에 공지된 방법을 사용하여 제형화될 수 있다. 제형은 분말, 과립, 정제, 에멀젼, 시럽, 에어로졸, 연질 또는 경질 젤라틴 캡슐, 멸균 주사용액, 멸균 분말일 수 있다.In addition, the composition of the present invention can be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a subject in need of treatment for atherosclerosis, including humans. can The dosage form may be a powder, granule, tablet, emulsion, syrup, aerosol, soft or hard gelatin capsule, sterile injectable solution, or sterile powder.
본 발명에 따른 약학적 조성물은 경구, 경피, 피하, 정맥 또는 근육을 포함한 여러 경로를 통해 투여될 수 있으며, 활성 성분의 투여량은 투여 경로, 환자의 연령, 성별, 체중 및 환자의 중증도 등의 여러 인자에 따라 적절히 선택될 수 있다. 또한, 신경발달장애 증상을 예방 또는 개선하는 효과를 가지는 공지의 화합물과 병행하여 투여할 수 있다.The pharmaceutical composition according to the present invention can be administered through various routes including oral, transdermal, subcutaneous, intravenous or intramuscular, and the dosage of the active ingredient depends on the route of administration, age, sex, weight and severity of the patient. It can be appropriately selected according to several factors. In addition, it can be administered in parallel with a known compound having an effect of preventing or ameliorating neurodevelopmental disorder symptoms.
나아가, 본 발명에 따른 상기 [화학식 1]로 표시되는 크산틴 유도체는 우수한 죽상동맥경화증 개선 효과를 통해 그 증상을 완화시키는 효과를 제공하고 있는 바, 독성 및 부작용 없이 장기간 복용시에도 안심하고 사용할 수 있는 장점이 있다.Furthermore, the xanthine derivative represented by [Formula 1] according to the present invention provides an effect of alleviating the symptoms through an excellent effect of improving atherosclerosis, and can be safely used even when taken for a long time without toxicity and side effects. There are advantages to being
건강기능식품용 조성물Composition for health functional food
본 발명의 하기 [화학식 1]로 표시되는 크산틴 유도체는 죽상동맥경화증의 예방 또는 개선을 목적으로 하는 식품에 첨가하여, 그 증상을 예방 또는 개선하기 위한 건강기능식품용 조성물로도 사용할 수 있다.The xanthine derivative represented by the following [Formula 1] of the present invention can be added to food for the purpose of preventing or improving atherosclerosis, and can also be used as a composition for health functional food to prevent or improve the symptoms.
[화학식 1][Formula 1]
상기 [화학식 1]에서 상기 X는 F, Cl 또는 Br이다.In [Formula 1], X is F, Cl or Br.
그러므로 본 발명에 따른 상기 [화학식 1]로 표시되는 크산틴 유도체는 죽상동맥경화증의 예방 및 개선에 효과가 있는 식품, 예컨대, 식품의 주원료, 부원료, 식품 첨가제, 기능성 식품 또는 음료의 제조에 용이하게 활용할 수 있다.Therefore, the xanthine derivative represented by [Chemical Formula 1] according to the present invention can be easily used in the production of foods effective in preventing and improving atherosclerosis, such as main ingredients, supplementary ingredients, food additives, functional foods or beverages. can be utilized
상기에서 "식품"이란, 영양소를 한 가지 또는 그 이상 함유하고 있는 천연물 또는 가공품을 의미하고, 바람직하게는 어느 정도의 가공 공정을 거쳐 직접 먹을 수 있는 상태가 된 것을 의미하며, 통상적인 의미로서 식품, 식품 첨가제, 기능성 식품 및 음료를 모두 포함하는 것을 말한다.In the above, "food" means a natural product or processed product containing one or more nutrients, and preferably means a product that can be eaten directly through a certain degree of processing process, and as a general meaning, food , food additives, functional foods and beverages.
본원발명에 따른 상기 [화학식 1]로 표시되는 크산틴 유도체를 유효성분으로 포함하는 조성물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 기능성 식품 등이 있다. 추가로, 상기 식품에는 특수영양식품(예, 조제유류, 영, 유아식 등), 식육가공품, 어육제품, 두부류, 묵류, 면류(예, 라면류, 국수류 등), 빵류, 건강보조식품, 조미 식품(예, 간장, 된장, 고추장, 혼합장 등), 소스류, 과자류(예, 스넥류), 캔디류, 쵸코렛류, 껌류, 아이스크림류, 유가공품(예, 발효유, 치즈 등), 기타 가공식품, 김치, 절임식품(각종 김치류, 장아찌 등), 음료(예, 과실 음료, 채소류 음료, 두유류, 발효음료류 등), 천연조미료(예, 라면 스프 등)가 포함되나 이에 한정되는 것은 아니며, 상기 식품, 음료 또는 식품첨가제는 통상의 제조방법으로 제조될 수 있다.Examples of foods to which the composition containing the xanthine derivative represented by Formula 1 according to the present invention as an active ingredient can be added include various foods, beverages, gum, tea, vitamin complexes, functional foods, etc. there is In addition, the above foods include special nutritional foods (eg, formula milk, infant food, baby food, etc.), processed meat products, fish meat products, tofu, jelly, noodles (eg, ramen, noodles, etc.), breads, health supplements, seasoning foods ( For example, soy sauce, soybean paste, gochujang, mixed paste, etc.), sauces, confectionery (eg, snacks), candies, chocolates, chewing gum, ice cream, dairy products (eg, fermented milk, cheese, etc.), other processed foods, kimchi, pickled foods (various types of kimchi, pickled vegetables, etc.), beverages (eg, fruit drinks, vegetable drinks, soy milk, fermented beverages, etc.), natural seasonings (eg, ramen soup, etc.), but are not limited thereto, and are not limited thereto. Additives can be prepared by conventional manufacturing methods.
또한, 상기 "기능성 식품"이란 식품에 물리적, 생화학적, 생물공학적 수법 등을 이용하여 해당 식품의 기능을 특정 목적에 작용, 발현하도록 부가가치를 부여한 식품군이나 식품 조성이 갖는 생체방어리듬조절, 질병방지와 회복 등에 관한 체내조절기능을 생체에 대하여 충분히 발현하도록 설계하여 가공한 식품을 의미하며, 바람직하게는 건강기능식품일 수 있다. 상기 기능성 식품에는 식품학적으로 허용 가능한 식품 보조 첨가제를 포함할 수 있으며, 기능성 식품의 제조에 통상적으로 사용되는 적절한 담체, 부형제 및 희석제를 더욱 포함할 수 있다.In addition, the above "functional food" refers to a food group or food composition that has added value so that the function of the food acts for a specific purpose by using physical, biochemical, or bioengineering methods, etc., to control biological defense rhythms and prevent diseases It means a food designed and processed to sufficiently express the body's regulatory functions related to recovery and recovery, preferably a health functional food. The functional food may include food additives that are acceptable in food science, and may further include appropriate carriers, excipients, and diluents commonly used in the manufacture of functional foods.
또한, 본원발명에서 상기 "음료"란 갈증을 해소하거나 맛을 즐기기 위하여 마시는 것의 총칭을 의미하며 기능성 음료를 포함한다. 상기 음료는 필수 성분으로서 혈소판 유래 성장 인자에 의한 혈관 평활근 세포 증식의 예방 또는 개선을 위한 상기 [화학식 1]로 표시되는 크산틴 유도체를 포함하는 조성물을 포함하는 것 외에 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다.In addition, in the present invention, the "beverage" refers to a general term for drinking to quench thirst or enjoy taste, and includes functional beverages. The beverage is not particularly limited in other ingredients except for including a composition containing the xanthine derivative represented by [Formula 1] for preventing or improving vascular smooth muscle cell proliferation by platelet-derived growth factor as an essential ingredient, and is usually It may contain various flavoring agents or natural carbohydrates as additional ingredients, such as beverages of.
이에 더하여, 상기 기술한 것 이외에 본원발명의 조성물을 함유하는 식품은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있으며, 상기 성분은 독립적으로 또는 조합하여 사용할 수 있다.In addition, foods containing the composition of the present invention other than those described above include various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring agents and fillers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. Can be used in combination.
본 발명에 따른 건강기능식품용 조성물을 함유하는 식품에 있어서, 상기 상기 [화학식 1]로 표시되는 크산틴 유도체를 유효성분으로 포함하는 조성물의 양은 전체 식품 중량의 0.01 중량% 내지 99.9 중량%로 포함할 수 있으며, 바람직하게는 0.1 중량% 내지 99 중량%로 포함할 수 있고, 음료의 경우, 100 ml를 기준으로 0.001 g 내지 2.0 g, 바람직하게는 0.01 g 내지 0.1 g의 비율로 포함할 수 있으며, 장기간 섭취 용도일 경우에는 상기 범위 이하일 수 있으나, 유효성분이 안전성 면에서 아무런 문제가 없기 때문에 상기 범위 이상의 양으로 사용될 수 있으므로 상기 범위에 한정되는 것은 아니다.In the food containing the composition for health functional food according to the present invention, the amount of the composition containing the xanthine derivative represented by [Formula 1] as an active ingredient is 0.01% to 99.9% by weight of the total weight of the food. It may be included, preferably in an amount of 0.1% to 99% by weight, and in the case of a beverage, it may be included in a ratio of 0.001 g to 2.0 g, preferably 0.01 g to 0.1 g based on 100 ml, , In the case of long-term intake use, it may be less than the above range, but since the active ingredient has no problem in terms of safety, it can be used in an amount greater than the above range, so it is not limited to the above range.
그러므로 본 발명은 상기 [화학식 1]로 표시되는 크산틴 유도체를 유효성분으로 함유하는 죽상동맥경화증 개선용 건강기능식품용 조성물을 제공할 수 있으며, 상기 식품의 형태는 이에 제한되지는 않으나, 분말, 과립, 정제, 캡슐 또는 음료 형태일 수 있다.Therefore, the present invention can provide a composition for health functional food for improving atherosclerosis containing the xanthine derivative represented by Formula 1 as an active ingredient, and the form of the food is not limited thereto, but powder, It can be in the form of granules, tablets, capsules or beverages.
죽상동맥경화증 치료제 및 이를 이용한 치료방법Atherosclerosis treatment and treatment method using the same
본 발명의 약학적 조성물은 죽상동맥경화증 개선 효과를 나타내다.The pharmaceutical composition of the present invention exhibits an effect of improving atherosclerosis.
그러므로, 본 발명은 또한 하기 [화학식 1]로 표시되는 크산틴 유도체를 죽상동맥경화증 치료제로서의 용도를 제공한다.Therefore, the present invention also provides a use of a xanthine derivative represented by the following [Formula 1] as a therapeutic agent for atherosclerosis.
[화학식 1][Formula 1]
상기 [화학식 1]에서 상기 X는 F, Cl 또는 Br이다.In [Formula 1], X is F, Cl or Br.
본 발명은 또한 포유동물에게 치료상 유효량의 상기 [화학식 1]로 표시되는 크산틴 유도체를 투여하는 단계를 포함하는 죽상동맥경화증 치료방법을 제공한다.The present invention also provides a method for treating atherosclerosis comprising administering a therapeutically effective amount of a xanthine derivative represented by Formula 1 to a mammal.
구체적으로, 본 발명의 상기 [화학식 1]로 표시되는 크산틴 유도체는 환자의 연령, 성별, 상태, 체중, 체내에 활성 성분의 흡수도, 불활성율 및 배설속도, 질병종류, 병용되는 약물에 따라 투여량이 달라질 수 있으나, 일반적으로는 체중 1 kg 당 1 내지 1000 mg, 바람직하게는 200 내지 600 mg을 투여할 수 있다.Specifically, the xanthine derivative represented by [Formula 1] of the present invention depends on the patient's age, sex, condition, body weight, absorption rate, inactivation rate and excretion rate of the active ingredient in the body, type of disease, and concomitant medication. Although the dosage may vary, generally 1 to 1000 mg, preferably 200 to 600 mg per 1 kg of body weight may be administered.
또한, 여기에서 사용된 용어 "포유동물"은 치료, 관찰 또는 실험의 대상인 포유동물을 말하며, 바람직하게는 인간을 말하며, "치료상 유효량"은 연구자, 수의사, 의사 또는 기타 임상의에 의해 생각되는 조직계, 동물 또는 인간에서 생물학적 또는 의학적 반응을 유도하는 유효 성분 또는 약학적 조성물의 양을 의미하는 것으로, 이는 치료되는 질환 또는 장애의 증상의 완화를 유도하는 양을 포함한다.In addition, the term "mammal" as used herein refers to a mammal that is a subject of treatment, observation, or experimentation, and preferably refers to a human, and "therapeutically effective amount" refers to an amount considered by a researcher, veterinarian, physician, or other clinician. An amount of an active ingredient or pharmaceutical composition that induces a biological or medical response in a tissue system, animal or human, including an amount that induces alleviation of symptoms of the disease or disorder being treated.
본 발명의 이점 및 특징, 그리고 그것들을 달성하는 방법은 상세하게 후술되어 있는 실시예들을 참조하면 명확해 질 것이다. 그러나, 본 발명은 이하에서 개시되는 실시예들에 한정되는 것이 아니라 서로 다른 다양한 형태로 구현될 수 있으며, 단지 실시예들은 본 발명의 개시가 완전하도록 하고, 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에게 발명의 범주를 완전하세 알려 주기 위해 제공되는 것이며, 본 발명은 청구항의 범주에 의해 정의될 뿐이다.Advantages and features of the present invention, and methods of achieving them, will become clear with reference to the embodiments described below in detail. However, the present invention is not limited to the embodiments disclosed below, but may be implemented in various different forms, and only the embodiments make the disclosure of the present invention complete, and common knowledge in the art to which the present invention belongs. It is provided to fully inform the person who has the scope of the invention, and the present invention is only defined by the scope of the claims.
[실시예][Example]
1. 동물실험 및 윤리 선언문 (Animal experimentation and ethics statement)1. Animal experimentation and ethics statement
동물과 관련된 모든 실험은 미국 국립보건원(NIH Publication No. 85-23, 2011 revision)에서 발행한 실험동물의 관리 및 사용에 대한 지침에서 제공한 지침을 준수하였다. 모든 동물 실험 프로토콜은 부산대학교 의과대학 동물보호 및 이용위원회(PNU-2020-2680)의 승인을 받았다. 본 발명은 Jackson Laboratory(Harlan Nossan, ITA)에서 제공한 프로토콜을 사용하여 PCR을 통해 PCK2 결핍 마우스를 포함한 유전자형 분석을 수행하였다. 본 발명은 Jackson Laboratory에서 C57BL/6J 야생형 대조군 마우스(WT)를 구입했다. 동물을 22-25°C의 에어컨이 설치된 방에 수용하고 12시간의 명암 주기로 유지하였고, 음식과 물은 임의로 제공되었다. 본 발명의 모든 인체 실험은 헬싱키 선언을 준수했으며 가천대학교 길병원 윤리위원회(GFIRB2020-085)의 현지 임명 윤리위원회의 승인을 받았으며, 모든 연구 참가자로부터 사전 동의를 얻었습니다.All experiments involving animals complied with the guidelines provided by the Guidelines for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, 2011 revision). All animal experimental protocols were approved by the Animal Care and Use Committee (PNU-2020-2680), Pusan National University School of Medicine. In the present invention, genotyping was performed including PCK2 deficient mice through PCR using a protocol provided by Jackson Laboratory (Harlan Nossan, ITA). In the present invention, C57BL/6J wild-type control mice (WT) were purchased from Jackson Laboratory. Animals were housed in an air-conditioned room at 22-25 °C and maintained on a 12-h light/dark cycle, with food and water provided ad libitum. All human experiments in this study complied with the Declaration of Helsinki and were approved by the locally appointed Ethics Committee of Gachon University Gil Hospital (GFIRB2020-085), and informed consent was obtained from all study participants.
2. 혈관 손상 모델 및 혈류 측정 (Vascular injury models and blood flow measurement)2. Vascular injury models and blood flow measurement
본 발명은 클로랄 수화물(chloral hydrate. 450mg/kg)의 복강 내 주사를 통해 WT 및 PCK2 결핍 수컷 마우스(7주령)를 마취하였다. 발가락 핀치에 대한 반응으로 마취 용량의 효율성을 확인했다. 그 후 앞서 설명한 대로 무균 조건에서 직경 0.25 mm의 혈관 성형술 가이드 와이어를 사용하여 오른쪽 대퇴 동맥에 부상을 입혔다. 손상 4주 후, 이산화탄소 주입과 경추 탈구로 안락사시킨 마우스로부터 철사로 손상된 대퇴동맥을 채취하였다. 분리된 대퇴동맥을 4 ℃에서 4% 파라포름알데히드(paraformaldehyde)에 밤새 고정하고 파라핀이 포매된 단면(4μm)을 준비하였다. 상기 조직 절편을 헤마톡실린(hematoxylin) 및 에오신(eosin, H&E) 및 면역조직학적 항체(immunohistological antibodies)로 염색하였다. 대퇴 동맥 손상 4주 후, 레이저 도플러 관류 영상(laser Doppler perfusion imaging, LDPI) 분석기(Moor Instruments, Devon, UK)를 사용하여 대퇴동맥의 혈류를 측정했다. 히스토그램 픽셀(histogram pixels)의 색상을 사용하여 혈류의 변화를 계산하였다.In the present invention, WT and PCK2 deficient male mice (7 weeks old) were anesthetized by intraperitoneal injection of chloral hydrate (450 mg/kg). We checked the effectiveness of the anesthetic dose in response to a toe pinch. The right femoral artery was then injured using an angioplasty guide wire with a diameter of 0.25 mm under aseptic conditions as previously described. Four weeks after the injury, the injured femoral artery was collected with a wire from a mouse euthanized by carbon dioxide injection and cervical dislocation. The isolated femoral artery was fixed in 4% paraformaldehyde at 4 °C overnight, and paraffin-embedded sections (4 μm) were prepared. The tissue sections were stained with hematoxylin and eosin (H&E) and immunohistological antibodies. Four weeks after femoral artery injury, femoral artery blood flow was measured using a laser Doppler perfusion imaging (LDPI) analyzer (Moor Instruments, Devon, UK). Changes in blood flow were calculated using the colors of histogram pixels.
3. 세포 배양3. Cell culture
인간 대동맥 혈관 평활근 세포(hVSMC)는 American Tissue Culture Collection(Manassas, VA, USA)에서 입수하였다. 본 발명은 평활근 세포 성장 배지(smooth muscle cell growth medium, Gibco BRL, Grand Island, NY, USA), 10% 소태아 혈청(10% fetal bovine serum), 1% 항생제-항진균 용액(1% antibiotic-antimycotic solution, Gibco BRL), 평활근 성장 보조제(smooth muscle growth supplement, Gibco BRL) 및 항생제-항진균제 용액(antibiotic-antimycotic solution, Gibco BRL)을 포함하는 배양 접시에서 hVSMC를 배양하였다. 세포는 5% CO2를 포함하는 가습된 대기에서 37°C에서 배양되었다.Human aortic vascular smooth muscle cells (hVSMC) were obtained from the American Tissue Culture Collection (Manassas, VA, USA). The present invention is a smooth muscle cell growth medium (Gibco BRL, Grand Island, NY, USA), 10% fetal bovine serum, 1% antibiotic-antimycotic solution (1% antibiotic-antimycotic solution, Gibco BRL), smooth muscle growth supplement (Gibco BRL), and antibiotic-antimycotic solution (Gibco BRL) were cultured in a culture dish containing hVSMC. Cells were incubated at 37°C in a humidified atmosphere containing 5% CO 2 .
4. 역전사 PCR 분석 (Reverse transcription (RT)-PCR analysis)4. Reverse transcription (RT)-PCR analysis
hVSMC에서 PCK2의 mRNA 발현은 내부 대조군으로 GAPDH를 사용하여 RT-PCR에 의해 정량화되었다. 제조사의 프로토콜에 따라 TRIzol 시약(Invitrogen, Carlsbad, NY, USA)을 사용하여 세포에서 총 RNA를 분리하였다. 분리된 RNA(1μg)는 ImProm-II 역전사 시스템(Promega, Madison, WI, USA)을 사용하여 cDNA로 역전사되었다. 이어서, PCK2-특이적 프라이머(앞으로, 5'-GGG TGC TAG ACT GGA TCT GC-3' 및 역방향, 5'-CTG GTT GAC CTG CTC TGT CA-3')를 사용하여 cDNA 증폭을 수행하였다. 동량(5㎕)의 RT-PCR 생성물을 에티듐 브로마이드(ethidium bromide)로 염색된 1% 아가로스 겔에서 분리하였다. PCR 산물은 UN-SCAN-IT GEL 7.1 프로그램을 이용하여 정량하였으며, GAPDH와 관련하여 PKC2의 mRNA 발현을 계산하였다.The mRNA expression of PCK2 in hVSMC was quantified by RT-PCR using GAPDH as an internal control. Total RNA was isolated from cells using TRIzol reagent (Invitrogen, Carlsbad, NY, USA) according to the manufacturer's protocol. Isolated RNA (1 μg) was reverse transcribed into cDNA using the ImProm-II reverse transcription system (Promega, Madison, WI, USA). Then, cDNA amplification was performed using PCK2-specific primers (forward, 5'-GGG TGC TAG ACT GGA TCT GC-3' and reverse, 5'-CTG GTT GAC CTG CTC TGT CA-3'). Equal amounts (5 μl) of RT-PCR products were separated on a 1% agarose gel stained with ethidium bromide. PCR products were quantified using the UN-SCAN-IT GEL 7.1 program, and the mRNA expression of PKC2 in relation to GAPDH was calculated.
5. 소형 간섭 RNA(siRNA) 준비 및 형질 감염 (Small interfering RNA (siRNA) preparation and transfection)5. Small interfering RNA (siRNA) preparation and transfection
PCK2용 siRNA를 설계 및 합성하고 AccuTarget siRNA 구성 키트(Bioneer, Daejeon, Korea)를 사용하여 음성 대조군(Cat no. SN-1003)으로 scrambled siRNA를 설계하였다. 모든 siRNA 분자는 제조업체의 프로토콜에 따라 Lipofectamine 2000(Invitrogen)을 사용하여 세포막의 기공을 통해 형질감염되었다.siRNA for PCK2 was designed and synthesized, and scrambled siRNA was designed as a negative control (Cat no. SN-1003) using the AccuTarget siRNA construction kit (Bioneer, Daejeon, Korea). All siRNA molecules were transfected through the pores of the cell membrane using Lipofectamine 2000 (Invitrogen) according to the manufacturer's protocol.
6. RNA 추출, 라이브러리 구축 및 시퀀싱 (RNA extraction, library construction, and sequencing)6. RNA extraction, library construction, and sequencing
형질감염된 hVSMC에서 총 RNA(0.5μg)는 제조업체의 프로토콜에 따라 TRIzol 시약 키트(Invitrogen)를 사용하여 추출되었으며, RNA 무결성은 TapStation RNA 스크린 테이프를 사용하여 평가되었다. 총 RNA 추출 후 Illumina TruSeq Stranded Total RNA Library Prep Gold Kit(Illumina, Inc., San Diego, CA, USA)를 사용하여 RNA 라이브러리를 독립적으로 준비하였다. 절단된 RNA 단편은 무작위 프라이머(Invitrogen)를 사용하여 SuperScript II 역전사효소(Invitrogen, Carlsbad, CA, USA)를 사용하여 첫 번째 가닥 cDNA로 복사되었다. 적격 cDNA 라이브러리는 Illumina NovaSeq 플랫폼(Illumina, Inc., San Diego, CA, USA)에서 시퀀싱되었다.Total RNA (0.5 μg) from transfected hVSMC was extracted using the TRIzol reagent kit (Invitrogen) according to the manufacturer's protocol, and RNA integrity was assessed using TapStation RNA screen tape. After total RNA extraction, an RNA library was independently prepared using the Illumina TruSeq Stranded Total RNA Library Prep Gold Kit (Illumina, Inc., San Diego, CA, USA). The digested RNA fragments were copied into first-strand cDNA using SuperScript II reverse transcriptase (Invitrogen, Carlsbad, CA, USA) using random primers (Invitrogen). Qualified cDNA libraries were sequenced on the Illumina NovaSeq platform (Illumina, Inc., San Diego, CA, USA).
7. RNA 시퀀싱 분석 (RNA-seq analysis)7. RNA sequencing analysis (RNA-seq analysis)
RNA-seq 분석을 수행하기 전, 시퀀서에서 얻은 원시 리드를 전처리하여 저품질 리드 및 어댑터 서열을 제거했다. HISAT v2.1.0(1)을 사용하여 처리된 읽기를 Homo sapiens(hg38) 게놈 시퀀스에 정렬했다. 이 참조 게놈 및 관련 주석 데이터는 University of California Santa Cruz 테이블 브라우저에서 다운로드되었다(http://genome.uscs.edu). 정렬 후, StringTie v1.3.4d를 사용하여 정렬된 읽기를 전사체로 조합하고 각 샘플에서 그 풍부함을 추정했다. 각 샘플에서 발현된 전사체 및 유전자의 읽기 카운트 값으로 전사체의 상대적 풍부함을 추정하였다.Prior to performing RNA-seq analysis, raw reads obtained from the sequencer were preprocessed to remove low quality reads and adapter sequences. The processed reads were aligned to the Homo sapiens (hg38) genome sequence using HISAT v2.1.0(1). This reference genome and associated annotation data were downloaded from the University of California Santa Cruz table browser (http://genome.uscs.edu). After alignment, the aligned reads were assembled into transcripts using StringTie v1.3.4d and their abundance was estimated in each sample. The relative abundance of transcripts was estimated from the read count values of the transcripts and genes expressed in each sample.
8. MTT 분석 (MTT assay)8. MTT assay
hVSMC의 증식 속도는 MTT 분석을 사용하여 분석되었다. 간단히 말해서, 1 × 105 세포를 MTT 작업 용액(EZ-Cytox, Daeil Laboratories, Seoul, 대한민국)으로 처리한 다음 5% CO2를 포함하는 가습 분위기에서 37°C에서 1시간 동안 배양했다. 포르마잔 결정(formazan crystals)의 광학 밀도는 마이크로 플레이트 리더(TECAN SUNRISE, Mannedorf, Switzerland)를 사용하여 450 nm에서 측정되었다. PDGF 처리된 세포와 대조군 세포를 비교하여 상대적 증식 속도를 분석하였다.The proliferation rate of hVSMCs was analyzed using the MTT assay. Briefly, 1 × 10 5 cells were treated with MTT working solution (EZ-Cytox, Daeil Laboratories, Seoul, Korea) and then incubated for 1 hour at 37°C in a humidified atmosphere containing 5% CO 2 . The optical density of formazan crystals was measured at 450 nm using a microplate reader (TECAN SUNRISE, Mannedorf, Switzerland). Relative proliferation rates were analyzed by comparing PDGF-treated cells with control cells.
9. 면역형광 분석 (Immunofluorescence analysis)9. Immunofluorescence analysis
본 발명은 대퇴동맥(femoral arteries)의 직렬 파라핀 섹션(serial paraffin sections)(4μm)을 마우스 항-α-SMA(1:400) 및 rabbit-anti PCK2 (1:200), rabbit-anti RGS1 (1:200), rabbit-anti AMPD3 (1:200), rabbit-anti KIAA1671 (1:200), goat-anti FHL1 (1:200) 또는 rabbit-anti LAMA5 (1:200) 항체와 함께 배양하였다. Goat anti-mouse Alexa488 접합 IgG 및 Goat anti-mouse Alexa594 접합 IgG 또는 Donkey anti-goat Alexa 594 접합 IgG(Abcam)를 사용하여 PCK2에 대한 면역형광 신호를 검출하였다. 핵을 0.1μg/mL의 DAPI로 염색하여 시각화한 후 벡타쉴드(Vectashield)에 슬라이드가 장착하였다. 스캐닝 공초점 현미경(scanning confocal microscope, LSM 510, Carl Zeiss, Oberkochen, Germany)을 사용하여 형광 이미지를 시각화하였다.In the present invention, serial paraffin sections (4 μm) of femoral arteries were prepared with mouse anti-α-SMA (1:400), rabbit-anti PCK2 (1:200), rabbit-anti RGS1 (1 :200), rabbit-anti AMPD3 (1:200), rabbit-anti KIAA1671 (1:200), goat-anti FHL1 (1:200) or rabbit-anti LAMA5 (1:200) antibodies. Immunofluorescence signals for PCK2 were detected using Goat anti-mouse Alexa488 conjugated IgG and Goat anti-mouse Alexa594 conjugated IgG or Donkey anti-goat Alexa 594 conjugated IgG (Abcam). Nuclei were visualized by staining with 0.1 μg/mL of DAPI, and then the slides were mounted on Vectashield. Fluorescent images were visualized using a scanning confocal microscope (LSM 510, Carl Zeiss, Oberkochen, Germany).
10. 통계 분석 (Statistical analysis)10. Statistical analysis
결과는 평균 ± SEM으로 표시된다. 일원 분산 분석(One-way analysis of variance, ANOVA)에 이어 Dunnett의 다중 비교 테스트를 사용하여 실험 결과의 중요성을 결정하였다. 수득된 데이터는 GraphPad Prism 버전 5.5.01을 사용하여 분석(GraphPad Software, USA)되었으며, 통계적 유의성은 p < 0.05로 설정되었다.Results are expressed as mean ± SEM. One-way analysis of variance (ANOVA) followed by Dunnett's multiple comparison test was used to determine the significance of experimental results. The data obtained were analyzed using GraphPad Prism version 5.5.01 (GraphPad Software, USA), and statistical significance was set at p < 0.05.
11. 인간 대퇴부 아테롬 샘플링 (Human femoral atheroma sampling)11. Human femoral atheroma sampling
가천대학교 길병원에서 일반 대퇴부 동맥내막 절제술을 받은 5명의 환자가 본 발명에 참여하였다. 수술실의 참가자들로부터 대퇴부 동맥내막 절제술 샘플을 수집하고 조직학적 검사를 위해 즉시 액체 질소에 동결시켰다. 조직 고정, H&E 염색 및 면역형광 염색은 이전 섹션에서 언급한 대로 수행되었다.Five patients who underwent general femoral endarterectomy at Gachon University Gil Hospital participated in the present invention. Femoral endarterectomy samples were collected from participants in the operating room and immediately frozen in liquid nitrogen for histological examination. Tissue fixation, H&E staining and immunofluorescence staining were performed as mentioned in the previous section.
[실험예][Experimental Example]
1. PCK2의 발현과 손상된 혈관에서 신생내막 증식 사이의 관련성 확인1. Confirmation of the relationship between PCK2 expression and neointimal proliferation in damaged blood vessels
손상된 대퇴동맥(femoral arteries) 혈관과 PCK2 발현 사이의 관련성을 입증하기 위해, 상기 대퇴동맥 혈관이 손상된 마우스와 혈관이 손상되지 않은 대조군(TW)에 대해 PCK2 발현을 면역형광법을 통해 확인하였으며, 이를 도 1에 나타내었다.In order to prove the relationship between damaged femoral arteries blood vessels and PCK2 expression, PCK2 expression was confirmed by immunofluorescence in mice with damaged femoral arteries and controls (TW) with intact blood vessels, which helped 1.
도 1을 참조하면, 대퇴동맥 혈관이 손상된 마우스가 혈관이 손상되지 않은 대조군(TW)과 비교하여 PCK2 발현이 높게 나타나는 것을 확인할 수 있다. Referring to Figure 1, it can be seen that PCK2 expression is higher in mice with damaged femoral artery blood vessels than in the control group (TW) with intact blood vessels.
상기 결과를 통해, 대퇴동맥 혈관이 손상된 경우 PCK2 발현이 상승됨이 입증한 것이라 할 수 있다.Through the above results, it can be said that PCK2 expression is elevated when the femoral artery is damaged.
2. 혈소판 유래 성장 인자와 혈관 평활근 세포 상관관계 확인2. Confirmation of correlation between platelet-derived growth factor and vascular smooth muscle cells
혈소판 유래 성장 인자와 혈관 평활근 세포 사이의 상관관계를 확인하기 위해, MTT 분석을 수행하였으며, 이를 도 2에 나타내었다.In order to confirm the correlation between platelet-derived growth factor and vascular smooth muscle cells, MTT analysis was performed, which is shown in FIG. 2 .
도 2를 참조하면, 혈소판 유래 성장 인자(24시간 동안 10 ng/ml)가 혈관 평활근 세포 증식을 증가시키는 것을 확인할 수 있다. 특히, 혈관 평활근 세포 증식의 이러한 혈소판 유래 성장 인자 유도 증가는 PCK2 siRNA에 의해 상당히 약화되었다. Referring to FIG. 2 , it can be confirmed that platelet-derived growth factor (10 ng/ml for 24 hours) increases vascular smooth muscle cell proliferation. Notably, this platelet-derived growth factor-induced increase in vascular smooth muscle cell proliferation was significantly attenuated by PCK2 siRNA.
3. [화학식 1]로 표시되는 크산티 유도체의 인간 혈관 평활근 세포(human VSMCs, hVSMC) 증식 억제 확인3. Confirmation of inhibition of human vascular smooth muscle cell (human VSMCs, hVSMC) proliferation by xanthi derivatives represented by [Formula 1]
상기 실험예 1 및 2를 통해 혈소판 유래 성장 인자와 혈관 평활근 세포 사이의 상관관계와 손상된 대퇴동맥(femoral arteries) 혈관과 PCK2 발현 사이의 상관관계를 통해, PCK2의 발현을 억제하면 혈소판 유래 성장 인자(Platelet Derived Growth Factor, PDGF)로 유도된 혈관 평활근 세포(Vascular Smooth Muscle Cells, VSMCs)의 증식을 억제할 수 있음을 확인하였다.Through the correlation between platelet-derived growth factor and vascular smooth muscle cells and the correlation between damaged femoral arteries blood vessels and PCK2 expression through Experimental Examples 1 and 2, suppression of PCK2 expression results in platelet-derived growth factor ( It was confirmed that the proliferation of Vascular Smooth Muscle Cells (VSMCs) induced by Platelet Derived Growth Factor (PDGF) could be inhibited.
본 발명은 본 발명에 따른 하기 [화학식 1로 표시되는 크산틴 유도체가 혈소판 유래 성장 인자로 유도된 인간 혈관 평활근 세포(human VSMCs, hVSMC)의 증식을 억제시킴을 확인하였으며, 이를 도 3에 나타내었다.The present invention confirmed that the xanthine derivative represented by the following [Formula 1] inhibits the proliferation of human vascular smooth muscle cells (human VSMCs, hVSMC) induced by platelet-derived growth factor according to the present invention, which is shown in FIG. 3 .
[화학식 1][Formula 1]
도 3을 참조하면, 본 발명에 따른 상기 [화학식 1]로 표시되는 크산틴 유도체가 혈소판 유래 성장 인자로 유도된 인간 혈관 평활근 세포의 증식을 약화시킴을 확인할 수 있다.Referring to FIG. 3 , it can be confirmed that the xanthine derivative represented by Formula 1 according to the present invention attenuates the proliferation of human vascular smooth muscle cells induced by platelet-derived growth factor.
상기 결과를 통해, 본 발명에 따른 [화학식 1]로 표시되는 크산틴 유도체가 죽상동맥경화증의 예방 또는 치료에 적용될 수 있음을 확인할 수 있다.Through the above results, it can be confirmed that the xanthine derivative represented by [Formula 1] according to the present invention can be applied to the prevention or treatment of atherosclerosis.
이상 설명으로부터, 본 발명에 속하는 기술 분야의 당업자는 본 발명의 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며, 한정적인 것이 아닌 것으로서 이해해야만 한다.From the above description, those skilled in the art pertaining to the present invention will be able to understand that the present invention can be implemented in other specific forms without changing its technical spirit or essential features. In this regard, the embodiments described above are illustrative in all respects and should be understood as non-limiting.
Claims (6)
- 하기 [화학식 1]로 표시되는 크산틴 유도체를 유효성분으로 포함하는 것을 특징으로 하는 죽상동맥경화증 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating atherosclerosis, comprising a xanthine derivative represented by the following [Formula 1] as an active ingredient.[화학식 1][Formula 1]
상기 [화학식 1]에서 상기 X는 F, Cl 또는 Br이다.In [Formula 1], X is F, Cl or Br. - 제1항에 있어서,According to claim 1,상기 약학적 조성물은 상기 약학적 조성물 총 중량% 대비 상기 [화학식 1]로 표시되는 크산틴 유도체를 0.01 중량% 내지 99.9 중량%로 포함하는 것을 특징으로 하는 약학적 조성물.The pharmaceutical composition is a pharmaceutical composition characterized in that it comprises 0.01% by weight to 99.9% by weight of the xanthine derivative represented by the [Formula 1] relative to the total weight% of the pharmaceutical composition.
- 제1항에 있어서,According to claim 1,상기 약학적 조성물은 혈소판 유래 성장 인자(Platelet Derived Growth Factor, PDGF)로 유도된 혈관 평활근 세포(Vascular Smooth Muscle Cells, VSMCs)의 증식을 감소시키는 것을 특징으로 하는 약학적 조성물.The pharmaceutical composition is a pharmaceutical composition, characterized in that for reducing the proliferation of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor (Platelet Derived Growth Factor, PDGF).
- 제1항에 있어서,According to claim 1,상기 약학적 조성물은 PCK2의 증식을 감소시키는 것을 특징으로 하는 약학적 조성물.The pharmaceutical composition characterized in that the pharmaceutical composition reduces the proliferation of PCK2.
- 하기 [화학식 1]로 표시되는 크산틴 유도체를 유효성분으로 포함하는 것을 특징으로 하는 죽상동맥경화증 예방 또는 개선용 건강기능식품용 조성물.A health functional food composition for preventing or improving atherosclerosis, characterized in that it comprises a xanthine derivative represented by the following [Formula 1] as an active ingredient.[화학식 1][Formula 1]
상기 [화학식 1]에서 상기 X는 F, Cl 또는 Br이다.In [Formula 1], X is F, Cl or Br. - 제5항에 있어서,According to claim 5,상기 건강기능식품용 조성물은 상기 건강기능식품용 조성물을 함유하는 건강기능식품 총 중량% 대비 상기 [화학식 1]로 표시되는 크산틴 유도체를 0.01 중량% 내지 99.9 중량%로 포함하는 것을 특징으로 하는 건강기능식품용 조성물.The health functional food composition comprises 0.01% to 99.9% by weight of the xanthine derivative represented by the [Formula 1] relative to the total weight% of the health functional food containing the composition for health functional food. A composition for nutraceuticals.
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| KR1020210146537A KR20230061860A (en) | 2021-10-29 | 2021-10-29 | Pharmaceutical composition for preventing or treating atherosclerosis comprising a xanthine derivative as an active ingredient |
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|---|---|---|---|---|
| WO2003106459A1 (en) * | 2002-06-12 | 2003-12-24 | F. Hoffmann-La Roche Ag | Amide substituted xanthine derivatives with gluconeogenesis modulating activity |
| WO2004074247A2 (en) * | 2003-02-19 | 2004-09-02 | Endacea, Inc. | A1 adenosine receptor antagonists |
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| KR101672708B1 (en) | 2015-09-14 | 2016-11-04 | 한림대학교 산학협력단 | - Food composition for improvement of atherosclerosis and pharmaceutical compositions for treatment of atherosclerosis with extract of Perilla frutescens or -asarone from Perilla frutescens |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2003106459A1 (en) * | 2002-06-12 | 2003-12-24 | F. Hoffmann-La Roche Ag | Amide substituted xanthine derivatives with gluconeogenesis modulating activity |
| WO2004074247A2 (en) * | 2003-02-19 | 2004-09-02 | Endacea, Inc. | A1 adenosine receptor antagonists |
Non-Patent Citations (3)
| Title |
|---|
| FOLEY L.H., ET AL: "Modified 3-Alkyl-1,8-dibenzylxanthines as GTP-Competitive inhibitors of phosphoenolpyruvate carboxykinase", BIOORGANIC & MEDICINAL CHEMISTRY LETTER, vol. 13, no. 20, 20 October 2003 (2003-10-20), Amsterdam NL , pages 3607 - 3610, XP008101995, ISSN: 0960-894X, DOI: 10.1016/S0960-894X(03)00722-4 * |
| HEGELE ROBERT A., AL-SHALI KHALID Z., HOUSE ANDREW A., HANLEY ANTHONY J.G., HARRIS STEWART B., MAMAKEESICK MARY, FENSTER AARON, ZI: "Disparate associations of a functional promoter polymorphism in PCK1 with carotid wall ultrasound traits", STROKE, vol. 36, no. 12, 1 December 2005 (2005-12-01), US , pages 2566 - 2570, XP093060472, ISSN: 0039-2499, DOI: 10.1161/01.STR.0000190833.43791.be * |
| PIETRANICO, S.L. FOLEY, L.H. HUBY, N. YUN, W. DUNTEN, P. VERMEULEN, J. WANG, P. TOTH, K. RAMSEY, G. GUBLER, M.L.: "C-8 Modifications of 3-alkyl-1,8-dibenzylxanthines as inhibitors of human cytosolic phosphoenolpyruvate carboxykinase", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 17, no. 14, 19 June 2007 (2007-06-19), Amsterdam NL , pages 3835 - 3839, XP022119964, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2007.05.013 * |
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