KR101892577B1 - Composition for preventing or treating atherosclerosis comprising reblastatin derivation or pharmaceutical acceptable salts thereof - Google Patents
Composition for preventing or treating atherosclerosis comprising reblastatin derivation or pharmaceutical acceptable salts thereof Download PDFInfo
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- KR101892577B1 KR101892577B1 KR1020170051786A KR20170051786A KR101892577B1 KR 101892577 B1 KR101892577 B1 KR 101892577B1 KR 1020170051786 A KR1020170051786 A KR 1020170051786A KR 20170051786 A KR20170051786 A KR 20170051786A KR 101892577 B1 KR101892577 B1 KR 101892577B1
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- atherosclerosis
- present
- levulastatin
- composition
- preventing
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Abstract
Description
본 발명은 레블라스타틴 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는 죽상동맥경화증 및 이에 따른 죽상동맥경화증에 의한 합병증의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating atherosclerosis and a complication due to atherosclerosis, which comprises a levulastatin derivative or a pharmaceutically acceptable salt thereof.
죽상동맥경화증(atherosclerosis)은 죽상경화증과 동맥경화증을 모두 포함하는 개념으로, 세계적으로 높은 사망률을 가지는 질환으로 알려져 있으며, 국내에서도 사망원인 2~3위를 차지할 정도로 위험한 질환이다.Atherosclerosis is a concept that includes both atherosclerosis and atherosclerosis. It is known as a disease with a high mortality rate globally, and it is a dangerous disease which is the second or third cause of death in Korea.
혈액에 존재하는 저밀도 지단백 콜레스테롤 (LDL)이 혈관 내벽에 축적되고 산화되면서 LDL의 구성 성분인 콜레스테롤도 혈관 내에서 산화된다. 산화된 콜레스테롤은 염증을 일으키며, 상기 염증반응으로 단핵구가 혈관 내벽으로 이동하게 된다. 이 후 단핵구는 콜레스테롤 산화물에 의하여 혈관벽 내에서 활성화되어 염증을 보다 증폭시킨다. 이러한 일련의 과정을 통하여 단핵구가 혈관 내벽으로 지속적으로 이동함으로써 죽상동맥경화증이 발생하게 된다. Low-density lipoprotein cholesterol (LDL) in the blood accumulates and oxidizes in the blood vessel walls, and cholesterol, a component of LDL, is also oxidized in the blood vessels. Oxidized cholesterol causes inflammation, which causes the mononuclear cells to migrate to the vessel wall. Monocytes are then activated in the blood vessel walls by cholesterol oxides, which further amplify inflammation. Through such a series of processes, the monocyte is continuously moved to the inner wall of the blood vessel, resulting in atherosclerosis.
상기에서 확인할 수 있는 바와 같이, 단핵구의 이동은 죽상동맥경화의 발생 및 발달에 중추적 역할을 하므로 혈관 내벽으로의 단핵구 이동을 억제하여 죽상동맥경화증을 치료하는 방법에 대한 관심이 증가하고 있다. 특히 콜레스테롤 산화물의 일종인 27-하이드록시콜레스테롤은 (27-hydroxycholesterol)은 죽상경화 플락에서 가장 많이 존재하는 콜레스테롤 산화물로 염증세포(특히 단핵구, T 세포)의 이동을 촉진시키고 대식세포에 자극을 주어 산화 스트레스를 유도함으로써 세포의 사멸을 유발하는 것으로 알려져 있다.As can be seen from the above, since the movement of monocytes plays a pivotal role in the development and development of atherosclerosis, there is an increasing interest in a method for treating atherosclerosis by inhibiting monocyte migration to the inner wall of blood vessels. In particular, 27-hydroxycholesterol (27-hydroxycholesterol), one of the cholesterol oxides, is the most abundant cholesterol oxide in the atherosclerotic plaque, promoting the migration of inflammatory cells (especially monocytes, T cells) and stimulating macrophages It is known to induce cell death by inducing stress.
한편, 죽상동맥경화증이 발생한 부위에서는 CD137, CD105 및 CD166과 같은 표지인자를 발현함으로써 죽상동맥경화증을 보다 촉진시키므로 상기 인자들은 죽상동맥경화증의 발현을 확인할 수 있는 바이오마커로 사용된다. 특히, CD137(4-1BB)은 죽상동맥경화증이 발생한 부위에 존재하는 단핵구에서 다량 발현되는 바이오마커이고, CD105(endoglin)는 TGF-β 수용체로써 죽상경화증이 발생한 부위의 단핵구의 불안정화에 관여하는 것을 알려진 바이오마커이며, CD166(Alcam)은 죽상동맥경화 조직에 특이적으로 발현되는 것으로 알려진 바이오마커이다. 특히, 죽상동맥경화 동물모델에서 CD137이 감소되는 경우 죽상경화증이 약화되고, CD137을 활성화시키는 경우 혈관의 염증이 증가한다. 따라서 CD137은 죽상경화증 치료 표적 중 하나이다.On the other hand, in the area where atherosclerosis occurs, a marker such as CD137, CD105, and CD166 is expressed, thereby promoting atherosclerosis. Therefore, these factors are used as a biomarker for confirming the expression of atherosclerosis. In particular, CD137 (4-1BB) is a biomarker that is expressed in a large amount in monocytes that are present in atherosclerosis site, and CD105 (endoglin) is involved in destabilization of monocytes in a site where atherosclerosis occurs as a TGF- Is a known biomarker, and CD166 (Alcam) is a biomarker known to be specifically expressed in atherosclerotic tissue. In particular, a decrease in CD137 in an atherosclerotic animal model attenuates atherosclerosis, and activation of CD137 increases inflammation of the blood vessels. Thus, CD137 is one of the targets for the treatment of atherosclerosis.
따라서 본 발명자들은 죽상동맥경화증에 중요한 27-하이드록시콜레스테롤의 활성과 이에 따른 단핵구 이동을 특이적으로 억제하는 화합물에 대하여 연구하던 중, 본 발명의 레블라스타틴 유도체가 현저한 27-하이드록시콜레스테롤의 활성 억제 효과를 가짐을 발견하고, 본 발명을 완성하였다.Therefore, the inventors of the present invention have studied a compound specifically inhibiting the activity of 27-hydroxycholesterol and thus the monocyte migration, which is important for atherosclerosis, and found that the levulastatin derivative of the present invention has a remarkable activity of 27-hydroxycholesterol Inhibitory effect, and completed the present invention.
본 발명의 목적은 하기 화학식 1로 표시되는 레블라스타틴 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는, 죽상동맥경화증 예방 또는 치료용 조성물 및 치료 보조제를 제공하는 것이다.An object of the present invention is to provide a composition and a therapeutic aid for the prevention or treatment of atherosclerosis, which comprises a levulastatin derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
본 발명의 또 다른 목적은 하기 화학식 1로 표시되는 레블라스타틴 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는, 죽상동맥경화증에 의한 합병증의 예방 또는 치료용 조성물을 제공하는 것이다.Still another object of the present invention is to provide a composition for preventing or treating complications due to atherosclerosis, which comprises a levulastatin derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Chemical Formula 1]
여기서, here,
R1은 H 또는 OH이고, R < 1 > is H or OH,
R2는 H 또는 OH이고, R 2 is H or OH,
R3는 단일 결합 또는 이중 결합이다.R 3 is a single bond or a double bond.
상기 과제를 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 레블라스타틴 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는, 죽상동맥경화증 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating atherosclerosis, comprising a levulastatin derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 하기 화학식 1로 표시되는 레블라스타틴 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는, 죽상동맥경화증 예방 또는 개선용 건강기능식품 조성물을 제공한다.The present invention also provides a health functional food composition for preventing or ameliorating atherosclerosis, comprising a levulastatin derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 하기 화학식 1로 표시되는 레블라스타틴 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는, 죽상동맥경화증 치료 보조제를 제공한다.The present invention also provides a therapeutic agent for atherosclerosis comprising a levulastatin derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 하기 화학식 1로 표시되는 레블라스타틴 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는, 죽상동맥경화증에 의한 합병증의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for preventing or treating complications due to atherosclerosis, comprising a levulastatin derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 하기 화학식 1로 표시되는 레블라스타틴 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는, 죽상동맥경화증에 의한 합병증의 예방 또는 개선용 건강기능식품 조성물을 제공한다.The present invention also provides a health functional food composition for preventing or ameliorating a complication caused by atherosclerosis, which comprises a levulastatin derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Chemical Formula 1]
여기서, here,
R1은 H 또는 OH이고, R < 1 > is H or OH,
R2는 H 또는 OH이고, R 2 is H or OH,
R3는 단일 결합 또는 이중 결합이다.R 3 is a single bond or a double bond.
본 발명의 레블라스타틴 유도체 또는 이의 허용가능한 염은 죽상동맥경화증에 의하여 발현이 증가하는 27-하이드록시콜레스테롤에 의한 CCL2의 분비와 단핵구의 이동 및 관련 면역 인자의 발현을 억제하는 바, 죽상동맥경화증의 치료제, 건강기능식품, 치료 보조제 등으로 다양하게 활용될 수 있다는 이점이 있다. 더욱이 죽상동맥경화증의 심화로 인하여 발생될 수 있는 죽상동맥경화증에 의한 다양한 합병증의 예방 또는 치료 기능을 가지는 바, 죽상동맥경화증에 의한 합병증, 특히 허혈성 심장질환, 뇌졸중, 신부전 및 허혈성 사지질환의 치료제 및 건강기능식품 등으로 활용될 수 있다는 이점이 있다.The levulastatin derivative of the present invention or an acceptable salt thereof inhibits the secretion of CCL2 by 27-hydroxycholesterol, which increases expression by atherosclerosis, and the expression of monocyte migration and related immune factors, A health functional food, a therapeutic aid, and the like. Furthermore, it has a function of preventing or treating various complications due to atherosclerosis which may be caused by deepening of atherosclerosis, and it is a therapeutic agent for a complication caused by atherosclerosis, in particular ischemic heart disease, stroke, renal failure and ischemic limb disease It can be used as a functional food for health and the like.
도 1은 ELISA를 통한 본 발명의 레블라스타틴 유도체에 의한 CCL2의 억제 효과를 확인한 결과를 나타내는 도이다.
도 2는 트랜스웰 세포 이동 분석을 통한 본 발명의 레블라스타틴 유도체에 의한 단핵구 이동 억제 효과를 확인한 결과를 나타내는 도이다.
도 3은 유세포 분석을 통한 본 발명의 레블라스타틴 유도체에 의한 죽상동맥경화증 관련 면역 인자의 발현 변화를 확인한 결과를 나타내는 도이다. 구체적으로 도 3a는 CD105의 발현 변화, 도 3b는 CD137의 발현 변화 및 도 3c는 CD166의 발현 변화를 확인한 결과를 나타낸 도이다.FIG. 1 is a graph showing the results of confirming the inhibitory effect of CCL2 by the levulastatin derivative of the present invention through ELISA.
FIG. 2 is a graph showing the effect of inhibiting monocyte migration by the levulastatin derivative of the present invention through analysis of transwell cell migration. FIG.
FIG. 3 is a graph showing the results of confirming changes in expression of an atherosclerosis-related immune factor by the levulastatin derivative of the present invention through flow cytometry. Specifically, FIG. 3A shows the expression of CD105, FIG. 3B shows the expression of CD137, and FIG. 3C shows the expression of CD166.
본 발명은 레블라스타틴(reblastatin) 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는, 죽상동맥경화증 및 죽상동맥경화증 합병증의 예방 또는 치료용 조성물을 제공한다. The present invention provides a composition for preventing or treating atherosclerosis and atherosclerotic complications, comprising a reblastatin derivative or a pharmaceutically acceptable salt thereof.
이하 본 발명을 자세하게 설명한다.Hereinafter, the present invention will be described in detail.
일례로, 본 발명은 하기 화학식 1로 표시되는 레블라스타틴 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는, 죽상동맥경화증 예방 또는 치료용 약학적 조성물을 제공한다. For example, the present invention provides a pharmaceutical composition for preventing or treating atherosclerosis, comprising a levulastatin derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
본 발명에 있어서, 상기 레블라스타틴 유도체는 수용성 물질인 레블라스타틴(reblastatin)의 17번 탄소에 결합된 메톡시기(methoxyl group) 대신 수소 또는 수산화기(hydroxyl group)이 결합되어 있는 것이 특징으로, 모체가 다른 안사마이신계 항생제와 구조적으로 상이하며, 특히 레블라스타틴과도 화학 구조상의 차이가 존재하여 생체 내에서 다른 활성을 나타내는 것이 특징이다. 보다 구체적으로 상기 레블라스타틴 유도체는 하기 화학식 2 내지 5 중 어느 하나일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the levulastatin derivative is characterized in that hydrogen or a hydroxyl group is bonded instead of a methoxyl group bonded to carbon number 17 of levulastatin, which is a water-soluble substance, Is structurally different from other ansamycin antibiotics. Especially, there is a chemical structural difference with levulastatin, and it is characterized by exhibiting different activities in vivo. More specifically, the levulastatin derivative may be any one of the following formulas (2) to (5), but is not limited thereto.
[화학식 1][Chemical Formula 1]
여기서, here,
R1은 H 또는 OH이고, R < 1 > is H or OH,
R2는 H 또는 OH이고, R 2 is H or OH,
R3는 단일 결합 또는 이중 결합이다.R 3 is a single bond or a double bond.
[화학식 2](2)
[화학식 3](3)
[화학식 4][Chemical Formula 4]
[화학식 5][Chemical Formula 5]
본 발명에 있어서, '예방'은 조성물의 투여에 의해 죽상동맥경화증을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.In the present invention, " prevention " means any action that inhibits atherosclerosis by administration of the composition or delays the onset of atherosclerosis.
본 발명에 있어서, '개선'은 조성물의 투여에 의해 죽상동맥경화증에 의한 증세가 호전되거나 이롭게 변경하는 모든 행위를 의미한다.In the present invention, 'improvement' refers to any action that improves or alleviates symptoms due to atherosclerosis by administration of the composition.
본 발명에 있어서, '치료'는 조성물의 투여에 의해 죽상동맥경화증을 낫게하는 행위를 모두 의미한다.In the present invention, " treatment " means all of the actions of atherosclerosis by administration of the composition.
본 발명에 있어서, '죽상동맥경화증'은 혈관의 가장 안쪽 막에 콜레스테롤 침착이 일어나고, 동시에 혈관 내피세포의 증식이 일어나 혈관이 좁아지거나 막히게 되어 그 혈관이 말초로의 혈류 장애를 일으키는 질환으로, 죽상 경화증 또는 동맥 경화증을 모두 포함한다. In the present invention, 'atherosclerosis' is a disease in which cholesterol deposition occurs in the innermost part of a blood vessel, and at the same time, vascular endothelial cell proliferation occurs and blood vessels become narrowed or clogged, causing blood vessels to disturb blood flow to the peripheral blood. Sclerosis or atherosclerosis.
한편, 죽상동맥경화증이 발생된 조직에서는 27-하이드록시콜레스테롤이 높은 농도로 발견되는 것이 특징인데, 상기 27-하이드록시콜레스테롤은 CCL2의 분비를 증가시키고, 이에 따라 단핵구의 이동이 증가하며, 관련 케모카인의 발현이 증가한다. 또한 27-하이드록시콜레스테롤은 CD137의 발현을 증가시킨다. 따라서 상기 인자들의 발현 변화 및 단핵구의 이동 변화를 분석한 실험 결과를 종합하여 죽상동맥경화증의 예방, 개선 또는 치료 효과를 확인할 수 있다. 상기 내용과 죽상동맥경화증 간의 상관관계에 대해서는 상기 [선행기술문헌] 중 [비특허문헌] 내에서 보다 명확하게 확인할 수 있다.On the other hand, 27-hydroxycholesterol is found in high concentrations in tissues in which atherosclerosis has developed. The 27-hydroxycholesterol increases the secretion of CCL2, thereby increasing the migration of monocytes, Lt; / RTI > Also, 27-hydroxycholesterol increases the expression of CD137. Therefore, the prevention, amelioration or therapeutic effect of atherosclerosis can be confirmed by integrating the experimental results obtained by analyzing the expression changes of the factors and the movement of mononuclear cells. Correlation between the above contents and atherosclerosis can be confirmed more clearly in [Non-Patent Document] of the above-mentioned [Prior Art Document].
본 발명에 있어서, 상기 레블라스타틴 유도체를 포함하는 조성물은 죽상동맥경화와 밀접한 관계가 있는 27-하이드록시콜레스테롤의 활성을 억제하여 죽상동맥경화증을 예방, 개선 또는 치료하는 것을 특징으로 한다.In the present invention, the composition comprising the levulastatin derivative is characterized by inhibiting the activity of 27-hydroxycholesterol, which is closely related to atherosclerosis, to prevent, ameliorate or treat atherosclerosis.
본 발명에 있어서, 상기 조성물은 약학적으로 허용 가능한 첨가제를 더 포함할 수 있으며, 이때 약학적으로 허용 가능한 첨가제로는 전분, 젤라틴화 전분, 미결정셀룰로오스, 유당, 포비돈, 콜로이달실리콘디옥사이드, 인산수소칼슘, 락토스, 만니톨, 엿, 아라비아고무, 전호화전분, 옥수수전분, 분말셀룰로오스, 히드록시프로필셀룰로오스, 오파드라이, 전분글리콜산나트륨, 카르나우바납, 합성규산알루미늄, 스테아린산, 스테아린산마그네슘, 스테아린산알루미늄, 스테아린산칼슘, 백당 등이 사용될 수 있다. 본 발명에 따른 약학적으로 허용 가능한 첨가제는 상기 조성물에 대해 0.1 내지 90 중량부 포함되는 것이 바람직하나 이에 한정되는 것은 아니다.In the present invention, the composition may further comprise a pharmaceutically acceptable additive. Examples of the pharmaceutically acceptable additives include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, hydrogen phosphate Calcium carbonate, lactose, mannitol, sugar, arabic gum, pregelatinized starch, corn starch, powdered cellulose, hydroxypropylcellulose, opaques, starch glycolate sodium, carnauba wax, synthetic aluminum silicate, stearic acid, magnesium stearate, Calcium stearate, white sugar, etc. may be used. The pharmaceutically acceptable additives according to the present invention are preferably included in the composition in an amount of 0.1 to 90 parts by weight, but not limited thereto.
본 발명에 있어서, 상기 조성물은 실제 임상 투여시에 경구 또는 비경구의 여러 가지 제형으로 투여될 수 있는데, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제할 수 있으며, 당해 기술 분야에 알려진 적합한 제제는 문헌 (Remington's Pharmaceutical Science, 최근, Mack Publishing Company, Easton PA)에 개시되어 있는 것을 이용하는 것이 바람직하다. 상기 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 올리고당, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 물, 메틸히드록시 벤조에이트, 프로필히드록시 벤조에이트, 탈크, 마그네슘 스테아레이트, 광물유 등이 있다.In the present invention, the composition may be administered orally or parenterally in various clinical formulations. In the case of formulation, a diluent such as a filler, an extender, a binder, a wetting agent, a disintegrant, , And those suitable for use in the art are disclosed in Remington ' s Pharmaceutical Sciences (Mack Publishing Company, Easton PA). Examples of carriers, excipients and diluents that can be contained in the composition include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil and the like.
상기 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘 카보네이트(Calcium carbonate), 수크로스 (Sucrose) 또는 락토오스(Lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 또한, 상기 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. The solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, Lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Examples of the liquid preparation for oral administration include suspensions, solutions, emulsions and syrups. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like May be included.
상기 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜(Propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. 상기 비경구투여는 피부 외용 또는 복강 내 주사, 직장 내 주사, 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사 주입방식을 사용하여 이루어질 수 있다.The preparation for parenteral administration includes sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used as the non-aqueous solvent and suspension agent. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like. The parenteral administration can be carried out using an external or intraperitoneal injection, intramuscular injection, subcutaneous injection, intravenous injection, intramuscular injection or intra-thoracic injection.
상기 본 발명의 조성물은 약학적으로 유효한 양으로 투여될 수 있다.The composition of the present invention may be administered in a pharmaceutically effective amount.
용어 '약학적으로 유효한 양'은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 감염된 바이러스 종류, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다.The term " pharmaceutically effective amount " means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dosage level will vary depending on the species and severity, age, sex, Activity, sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including co-administered drugs, and other factors well known in the medical arts. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. And can be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without adverse effect, and can be easily determined by those skilled in the art.
본 발명에 있어서 사용되는 용어 '투여'는 임의의 적절한 방법으로 개체에게 소정의 본 발명의 조성물을 제공하는 것을 의미한다.The term " administration " as used in the present invention means to provide a certain composition of the present invention to an individual by any suitable method.
본 발명에 있어서, 상기 조성물은 개체에게 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관 내 주사에 의해 투여될 수 있다.In the present invention, the composition may be administered to a subject by various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine dural or intracerebral injection.
본 발명에 있어서, 상기 조성물은 죽상동맥경화증의 예방 또는 치료를 위하여 단독으로, 또는 수술, 방사선 치료, 호르몬 치료, 화학 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.In the present invention, the composition can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers for the prevention or treatment of atherosclerosis.
또 다른 예로, 본 발명은 하기 화학식 1로 표시되는 레블라스타틴 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는, 죽상동맥경화증 예방 또는 개선용 건강기능식품 조성물을 제공한다.As another example, the present invention provides a health functional food composition for preventing or ameliorating atherosclerosis, comprising a levulastatin derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Chemical Formula 1]
여기서, here,
R1은 H 또는 OH이고, R < 1 > is H or OH,
R2는 H 또는 OH이고, R 2 is H or OH,
R3는 단일 결합 또는 이중 결합이다.R 3 is a single bond or a double bond.
본 발명에 있어서, '건강기능식품'이란 식품에 물리적, 생화학적, 생물공학적 수법 등을 이용하여 해당 식품의 기능을 특정 목적에 작용, 발현하도록 부가가치를 부여한 식품군이나 식품 조성이 갖는 생체방어리듬조절, 질병 방지와 회복 등에 관한 체내조절기능을 생체에 대하여 충분히 발현하도록 설계하여 가공한 식품으로, 장기적으로 복용하였을 때 인체에 무해하여야 한다.In the present invention, the term 'health functional food' refers to a food group imparted with added value to function or express the function of the food by using physical, biochemical, biotechnological techniques or the like, or a bioactive rhythm control , Which is designed to express the body's controlling function sufficiently for the prevention and restoration of disease, and should be harmless to the human body when taken over a long period of time.
상기 건강기능식품에는 식품학적으로 허용 가능한 식품 보조 첨가제를 포함할 수 있으며, 건강기능식품의 제조에 통상적으로 사용되는 적절한 담체, 부형제 및 희석제를 더욱 포함할 수 있다.The health functional food may include food-acceptable food supplementary additives, and may further include suitable carriers, excipients and diluents conventionally used in the production of health functional foods.
본 발명의 건강기능식품 조성물을 식품 첨가물로 사용할 경우, 상기 조성물을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 일반적으로, 식품 또는 음료의 제조 시에 본 발명의 조성물은 원료에 대하여 15 중량% 이하, 바람직하게는 10 중량% 이하의 양으로 첨가된다. 그러나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.When the health functional food composition of the present invention is used as a food additive, the composition may be added as it is, or may be used together with other food or food ingredients, and may be suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (prevention, health or therapeutic treatment). In general, the composition of the present invention is added in an amount of not more than 15% by weight, preferably not more than 10% by weight based on the raw material, in the production of food or beverage. However, in the case of long-term intake for the purpose of health and hygiene or for the purpose of controlling health, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.
상기 건강기능식품의 종류에 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 건강기능식품의 예로는 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 해당 식품의 기능을 특정 목적에 작용, 발현하도록 부가가치를 부여한 식품군이나 식품 조성이 갖는 생체방어리듬조절, 질병 방지와 회복 등에 관한 체내조절기능을 생체에 대하여 충분히 발현하도록 설계된 식품을 모두 포함한다.There is no particular limitation on the kind of the health functional food. Examples of health functional foods to which the above substances can be added include dairy products including ice cream, various soups, drinks, tea, drinks, alcoholic beverages and vitamin complexes. And foodstuffs designed to fully express in vivo the function of controlling the body in terms of regulation of bio-defense rhythm of food composition, prevention and recovery of disease, and the like.
상기 외에 본 발명의 건강기능식품 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 포함할 수 있다. 그 밖에 본 발명의 식품 조성물은 천연 과일주스, 과일주스 음료 및 야채 음료의 제조를 위한 과육을 포함할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 크게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0.01 내지 0.1 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above, the health functional food composition of the present invention may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, , Alcohols, carbonating agents used in carbonated drinks, and the like. In addition, the food composition of the present invention may comprise flesh for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These components may be used independently or in combination. Although the ratio of such additives is not critical, it is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.
또한, 본 발명은 하기 화학식 1로 표시되는 레블라스타틴 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는, 죽상동맥경화증 치료 보조제를 제공한다.The present invention also provides a therapeutic agent for atherosclerosis comprising a levulastatin derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
본 발명에 있어서, '죽상동맥경화증 치료 보조제'란 당업계에서 일반적으로 사용되는 죽상동맥경화증 치료법의 효과를 증진시키기 위하여 보조적으로 사용될 수 있는 제재를 말하며, 본 발명에 의한 레블라스타틴 유도체를 사용함으로써 함께 사용하는 죽상동맥경화증 치료법의 효과를 증진시킬 수 있다.In the present invention, the term 'atherosclerosis therapy adjuvant' refers to a drug that can be used as an adjuvant to enhance the effect of the atherosclerosis treatment method commonly used in the art. By using the levulastatin derivative according to the present invention The effect of atherosclerosis therapy used together can be improved.
아울러, 상기 죽상동맥경화증 치료법은 증상의 경도, 약제에 대한흡수 속도(치료기간과 약물 투여 경로), 죽상동맥경화증 발생 위치 등의 죽상동맥경화증 치료법 선택 시 고려하는 일반적인 원칙하에 선택될 수 있다.In addition, the above-mentioned treatment for atherosclerosis can be selected under a general rule to be considered when selecting a treatment for atherosclerosis, such as the hardness of symptoms, the rate of absorption (medication period and drug administration route) to a drug, and the location of occurrence of atherosclerosis.
또 다른 예로, 본 발명은 하기 화학식 1로 표시되는 레블라스타틴 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는, 죽상동맥경화증에 의한 합병증의 예방 또는 치료용 약학적 조성물을 제공한다.As another example, the present invention provides a pharmaceutical composition for preventing or treating complications caused by atherosclerosis, comprising a levulastatin derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
또한, 본 발명은 하기 화학식 1로 표시되는 레블라스타틴 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는, 죽상동맥경화증에 의한 합병증의 예방 또는 개선용 건강기능식품 조성물을 제공한다.The present invention also provides a health functional food composition for preventing or ameliorating a complication caused by atherosclerosis, which comprises a levulastatin derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Chemical Formula 1]
여기서, here,
R1은 H 또는 OH이고, R < 1 > is H or OH,
R2는 H 또는 OH이고, R 2 is H or OH,
R3는 단일 결합 또는 이중 결합이다.R 3 is a single bond or a double bond.
본 발명에 있어서, 상기 죽상동맥경화증 합병증은 죽상동맥경화로 혈관이 좁아지거나, 혹은 막히게 되면 그 혈관이 담당하는 말초로의 혈액순환장애가 발생하여 나타내는 질병을 지칭한다. 예를 들어, 심장의 관상동맥이 막히면 협심증, 심근경색 등의 허혈성 심장질환이 발생하게 되고, 뇌동맥이나 경동맥이 막히면 뇌경색, 뇌출혈 등의 뇌졸중, 신동맥 및 신장쪽 말초혈관이 막히게 되면 신부전 및 허혈성 사지 질환이 발생하게 된다. 따라서 본 발명의 죽상동맥경화증 합병증은 허혈성 심장질환, 뇌졸중, 신부전 또는 허혈성 사지 질환일 수 있으나, 이에 제한되는 것은 아니고 죽상동맥경화증의 악화로 발생할 수 있는 혈관 관련 질환을 모두 포함할 수 있다.In the present invention, the atherosclerotic complication refers to a disease caused by atherosclerosis of the atherosclerotic artery resulting in narrowing or clogging of blood vessels and peripheral blood circulation disorder of the blood vessels. For example, when the coronary artery of the heart is clogged, ischemic heart disease such as angina pectoris and myocardial infarction occurs, and if the cerebral artery or carotid artery is blocked, stroke such as cerebral infarction, cerebral hemorrhage, and obstruction of the renal artery and kidney peripheral blood vessels may result in renal failure and ischemic limb disease . Therefore, the atherosclerotic complication of the present invention may be ischemic heart disease, stroke, kidney failure or ischemic limb disease, but it is not limited thereto and may include all of the vascular-related diseases that may be caused by aggravation of atherosclerosis.
중복되는 내용은 본 명세서의 복잡성을 고려하여 생락하며, 본 명세서에서 달리 정의되지 않은 용어들은 본 발명이 속하는 기술분야에서 통상적으로 사용되는 의미를 갖는 것이다.The redundant contents are taken into consideration in the complexity of the present specification, and terms not otherwise defined herein have the meanings commonly used in the art to which the present invention belongs.
이하, 본 발명의 이해를 돕기 위하여 실시예, 실험예 및 제조예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예, 실험예 및 제조예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예, 실험예 및 제조예에 한정되는 것은 아니다. 본 발명의 실시예, 실험예 및 제조예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.EXAMPLES Hereinafter, examples, experimental examples and production examples will be described in detail to facilitate understanding of the present invention. However, the following Examples, Experimental Examples and Preparation Examples are intended only to illustrate the contents of the present invention, and the scope of the present invention is not limited to the following Examples, Experimental Examples and Production Examples. The embodiments, examples, and examples of the present invention are provided to enable those skilled in the art to more fully understand the present invention.
실시예 1. 레블라스타틴(reblastatin) 유도체의 합성Example 1 Synthesis of a Rebrastatin Derivative
1-1. 화학식 2 및 6의 레블라스타틴 유도체의 합성1-1. Synthesis of levulastatin derivatives of formulas 2 and 6
하기 표 1 내 화학식 2 및 6의 레블라스타틴 유도체는 각각 스트렙토마이세스 하이그로스코피쿠스 AC11(Streptomyces hygroscopicus AC11)과 스트렙토마이세스 하이그로스코피쿠스 AC15(Streptomyces hygroscopicus AC15)를 사용하여 제조하였다. 이는 상기 [선행기술문헌] 중 [비특허문헌] 11번 및 12번 문헌에 상세하게 개시되어 있다.The levulastatin derivatives of Formulas 2 and 6 in the following Table 1 were prepared using Streptomyces hygroscopicus AC11 and Streptomyces hygroscopicus AC15, respectively. This is disclosed in detail in [Non-Patent Documents] Nos. 11 and 12 among the above-mentioned [Prior Art Documents].
이를 간략하게 기술하면, 우선, 상기 AC11 균주 및 AC15 균주 각각을 방선균배양 YEME 배지(yeast extract-malt extract medium)에서 28℃에서 7일간 배양하였고, 배양물 형태로 수득되는 추출물을 얻었다. 이 후 CHCl3-MeOH을 이동상으로 하여 실리카 겔 크로마토그래피를 이용하여 상기 추출물을 분획하였으며, 분획 결과 화학식 2 및 6의 화합물을 최종 수득하였다.In brief, each of the AC11 strain and the AC15 strain was cultured in a yeast extract-malt extract medium at 28 占 폚 for 7 days in order to obtain an extract obtained in the form of a culture. Then, the extract was fractionated using silica gel chromatography using CHCl 3 -MeOH as a mobile phase. As a result, the compounds of Formulas 2 and 6 were finally obtained.
수득한 분획물은 Waters Delta Prep 3000 system (Waters사, 미국)을 이용한 HPLC[YMC J'sphere ODS-H80, 150 x 4.6 mm i.d., MeOH-H2O(0.05% acetic acid) gradient, 1 ㎖/min]을 수행하여 최종적으로 그 구조를 분석하였고, 그 결과는 하기 표 1에 나타내었다. The obtained fractions were analyzed by HPLC (YMC J'sphere ODS-H80, 150 x 4.6 mm id, MeOH-H2O (0.05% acetic acid) gradient, 1 ml / min) using a Waters Delta Prep 3000 system And the structure thereof was finally analyzed. The results are shown in Table 1 below.
1-1. 화학식 3 내지 5의 레블라스타틴 유도체의 합성1-1. Synthesis of levulastatin derivatives of formulas 3 to 5
하기 표 1 내 화학식 3 내지 5의 레블라스타틴 유도체는 방선균 스트렙토마이세스 하이그로스코피쿠스 AC2(Streptomyces hygriscopicus AC2) 균주를 사용하여 제조하였다. 이는 상기 [선행기술문헌] 중 [비특허문헌] 13번 문헌에 상세하게 개시되어 있다. 한편, 상기 AC2 균주는 3-아미노-5-하이드록시벤조산(3-amino-5-hydroxylbenzoic acid; AHBA)을 생성하지 못하는 균이다. To re Blossom statin derivatives shown in Table 1 in the formula is 3 to 5 Actinomycetes Streptomyces high-gloss nose kusu AC2 (Streptomyces hygriscopicus AC2) strain. This is disclosed in detail in [Non-Patent Document] 13 of the above-mentioned prior art documents. On the other hand, the AC2 strain does not produce 3-amino-5-hydroxylbenzoic acid (AHBA).
이를 간략하게 기술하면, 우선, AC2 균주를 28℃에서 3일 동안 100 ㎖의 방선균배양 YEME 배지에서 배양하였다. 이 후 상기 배지의 배양액을 2 L의 YEME 배지에 옮긴 후 28℃에서 1일 더 배양하였으며, 이 후 700 ㎎의 3-아미노벤조익산(3-aminobenzoic acid) 첨가한 후 28℃에서 7일 더 배양하였다. 그리고나서 상기 배양 배지를 에틸 아세트산(EtOAc)으로 2회 반복 추출한 후, 이들 추출물을 여과하여 불용물을 제거하였다. 그리고 나서 여과된 추출물을 농축시키고, 농축액은 EtOAc와 H2O로 분획하여 유기상 추출물을 얻었다. 그 다음으로 상기 유기상 추출물을 CHCl3-MeOH을 이동상으로 하여 실리카 겔 크로마토그라피를 이용하여 분획하였으며, 분획 결과 화학식 3 내지 5의 화합물을 최종 수득하였다. Briefly, the AC2 strain was first cultured in 100 ml actinomycetes cultured YEME medium at 28 ° C for 3 days. After that, the culture medium of the medium was transferred to 2 L of YEME medium and further cultured at 28 ° C for 1 day. After that, 700 mg of 3-aminobenzoic acid was added, followed by further cultivation at 28 ° C for 7 days Respectively. Then, the culture medium was repeatedly extracted twice with ethyl acetate (EtOAc), and then the extract was filtered to remove insolubles. The filtered extract was then concentrated and the concentrate was partitioned between EtOAc and H 2 O to give an organic phase extract. Next, the organic phase extract was fractionated using silica gel chromatography using CHCl 3 -MeOH as a mobile phase, and the resulting compound was finally obtained as a compound of Formulas 3 to 5.
수득한 분획물은 Waters Delta Prep 30 00 system (Waters사, 미국)을 이용한 HPLC[YMC J'sphere ODS-H80, 150 x 4.6 mm i.d., MeOH-H2O(0.05% acetic acid) gradient, 1 ㎖/min]을 수행하여 최종적으로 그 구조를 분석하였고, 그 결과는 하기 표 1에 나타내었다.The obtained fractions were analyzed by HPLC (YMC J'sphere ODS-H80, 150 x 4.6 mm id, MeOH-H2O (0.05% acetic acid) gradient, 1 ml / min) using a Waters Delta Prep 30 00 system And the structure thereof was finally analyzed. The results are shown in Table 1 below.
17-dimethoxyl-levulastatin
18-dihydroxy-17-dimethoxyl-levulastatin
하기 실험예 1 내지 3을 통하여 27-하이드록시콜레스테롤의 활성 억제를 통한 우수한 죽상동맥경화증의 예방 또는 치료 효과가 있음을 확인한 화학식 2 내지 5의 화합물을 본 발명의 유효성분인 레블라스타틴 유도체로 최종 선별하였다.The compounds of the formulas (2) to (5), which were found to be effective for the prevention or treatment of excellent atherosclerosis through inhibition of the activity of 27-hydroxycholesterol through the following Experimental Examples 1 to 3, Respectively.
실험예Experimental Example 1. ELISA(enzyme-linked immunosorbent assay)를 통한 1. Through enzyme-linked immunosorbent assay (ELISA) 레블라스타틴Levulastatin 유도체의 CCL2(chemokine (C-C motif) ligand 2)의 억제 효과 확인 Identification of inhibitory effects of CCL2 (chemokine (C-C motif) ligand 2) on derivatives
ELISA를 이용하여 본 발명의 레블라스타틴 유도체의 죽상동맥경화증 억제 효과, 특히 단핵구의 이동을 촉진하는 CCL2의 억제 효과를 확인하는 실험을 수행하였다. 본 발명에 사용한 THP-1 단핵구 세포(ATCCⓡTIB-202TM)는 ATCC(American Type Culture Collection)사로부터 구매하였으며, 함께 제공받은 메뉴얼에 따라 THP-1 세포를 배양하였다. 그리고 이하의 실험은 BD Biosciences사의 BD OptEIA TM Hunan MCP-1 ELISA Kit (cat# 559017)를 이용하여 수행하였다. An experiment was conducted to confirm the inhibitory effect of the levulastatin derivative of the present invention on atherosclerosis-suppressing effect of CCL2, which promotes the migration of monocytes, using ELISA. THP-1 monocyte cells (ATCC ⓡ TIB-202 TM ) used in the present invention were purchased from ATCC (American Type Culture Collection), and THP-1 cells were cultured according to the provided manual. The following experiments were carried out using BD OptEIA ™ Hunan MCP-1 ELISA Kit (Cat # 559017) from BD Biosciences.
구체적으로, 본 실험은 THP-1 세포를 7개의 실험군으로 나눈 후 각각에 27-하이드록시콜레스테롤(27OH, Santa Cruz Biotechnology사)과 상기 실시예 1에서 제조한 1 μg/ml의 화학식 2 내지 6 중 어느 하나를 함께 처리한 후 배양하였다. 또한, 하나의 실험군은 음성대조군으로서 어떤 것도 처리하지 않고 배양만을 수행하였고, 나머지 하나의 실험군은 양성대조군으로서 27-하이드록시콜레스테롤만을 처리한 후 배양하였다. 배양은 약물 처리 후 48시간 동안 수행하였다. 이 후 원심분리를 통하여 배지와 세포를 분리하였으며, 분리한 배지 100 μL를 1차 항체인 CCL2 항체가 코팅되어있는 마이크로플레이트에 넣고 2시간 동안 배양하였다. 이 후 배지를 제거하였으며, 제거 후에도 마이크로플레이트에 결합된 CCL2에 2차 항체인 홀스래디쉬 과산화효소가 부착된 항체를 넣고 1시간 동안 배양하였다. 상기 1차 항체 및 2차 항체는 상기 ELISA 키트에서 제공하는 항체를 사용하였다. Specifically, in this experiment, THP-1 cells were divided into 7 experimental groups and 27-hydroxycholesterol (27OH, manufactured by Santa Cruz Biotechnology) and 1 μg / ml of the compounds of Formulas 2 to 6 One was treated together and then cultured. In addition, one test group was cultured without any treatment as a negative control group, and the other test group was treated with only 27-hydroxycholesterol as a positive control group and then cultured. Cultivation was performed for 48 hours after drug treatment. After that, the culture medium and cells were separated by centrifugation. 100 μL of the separated culture medium was put into a microplate coated with CCL2 antibody as a primary antibody and cultured for 2 hours. Subsequently, the medium was removed and CCL2 bound to a microplate was incubated with an antibody with a secondary antibody, horseradish peroxidase, for 1 hour. The primary and secondary antibodies used were the antibodies provided in the ELISA kit.
그리고 나서 항체를 제거하고 본 실험에 사용한 키트에서 제공하는 기질용액을 처리하는 일련의 과정을 수행한 후 마이크로플레이트 리더를 이용하여 측정하였다. 이 후 측정된 흡광도를 실험에 사용한 키트에서 제공하는 표준곡선에 대입하여 CCL2 농도를 계산하였다. 그 결과를 그래프화하여 도 1에 나타내었다. (P<0.001; ***, P<0.001; ###)Then, the antibody was removed, and a series of steps of treating the substrate solution provided in the kit used in the present experiment was performed, and then the measurement was performed using a microplate reader. The measured absorbance was then substituted into the standard curve provided in the kit used for the experiment to calculate the CCL2 concentration. The results are shown graphically in FIG. (P <0.001; ***, P <0.001;###)
도 1에 나타낸 바와 같이, 양성 대조군에서는 27-하이드록시콜레스테롤 처리에 의하여 대식세포에서의 CCL2의 분비량이 현저하게 증가함을 확인하였다. 이 후 화학식 2 내지 5의 화합물을 처리한 경우에는 CCL2 분비량이 음성 대조군의 경우와 유사한 수준까지 감소하는 것을 확인하였다. 다만, 화학식 6의 화합물을 처리한 경우에는 화학식 2 내지 5의 화합물을 처리한 경우와 달리 CCL2 분비량의 수준이 감소하지 않고, 양성대조군의 CCL2 분비량과 비슷한 수준으로 유지됨을 확인하였다. 이는 본 발명의 레블라스타틴 유도체가 특이적으로 27-하이드록시콜레스테롤의 활성에 의한 대식세포에서의 CCL2 분비량을 억제함을 나타낸다.As shown in Fig. 1, in the positive control group, it was confirmed that the secretion amount of CCL2 in the macrophage was remarkably increased by the treatment with 27-hydroxycholesterol. When the compounds of the formulas (2) to (5) were subsequently treated, it was confirmed that the amount of CCL2 secretion was reduced to a level similar to that of the negative control. However, when the compound of Chemical Formula 6 was treated, it was confirmed that the level of CCL2 secretion was not decreased unlike the case of treating the compounds of Chemical Formula 2 to 5, and maintained at a level similar to that of positive control CCL2. This shows that the levulastatin derivative of the present invention specifically inhibits CCL2 secretion in macrophages by the activity of 27-hydroxycholesterol.
실험예Experimental Example 2. 2. 트랜스웰Transwell 세포 이동 분석( Cell migration analysis ( TranswellTranswell cell migration assay)을 통한 cell migration assay 레블라스타틴Levulastatin 유도체의 단핵구 이동 억제 효과 확인 Identification of inhibitory effect of derivatives on monocyte migration
트랜스웰 세포 이동 분석(transwell permeable support; costar 사)을 통한 본 발명의 레블라스타틴 유도체의 죽상동맥경화증 억제 효과, 특히 단핵구의 이동을 억제하는 효과를 확인하는 실험을 수행하였다. 본 발명에 사용한 THP-1 단핵구 세포(ATCCⓡTIB-202TM)는 ATCC(American Type Culture Collection)사로부터 구매하였으며, 함께 제공받은 메뉴얼에 따라 THP-1 세포를 배양하였다.Experiments were carried out to confirm the effect of the levulastatin derivative of the present invention on the inhibition of atherosclerosis, in particular the inhibition of the migration of monocytes, through a transwell permeable support (Costar). THP-1 monocyte cells (ATCC ⓡ TIB-202 TM ) used in the present invention were purchased from ATCC (American Type Culture Collection), and THP-1 cells were cultured according to the provided manual.
구체적으로, 본 실험은 THP-1 세포를 7개의 실험군으로 나눈 후 각각에 27-하이드록시콜레스테롤(27OH, Santa Cruz Biotechnology사)과 상기 실시예 1에서 제조한 1 μg/ml의 화학식 2 내지 6 중 하나를 함께 처리한 후 배양하였다. 또한, 하나의 실험군은 음성대조군으로서 어떤 것도 처리하지 않고 배양만을 수행하였고, 나머지 하나의 실험군은 양성대조군으로서 27-하이드록시콜레스테롤만을 처리한 후 배양하였다. 배양은 약물 처리 후 48시간 동안 수행하였다. 이 후 원심분리를 통하여 배지와 세포를 분리하였으며, 분리한 배지를 아래쪽 챔버에 분주하였다. 한편, 트랜스웰의 위쪽 챔버에 100 μl의 BSA(0.1%) 내에 함유된 THP-1 세포 5×105개를 분주하였다. 이 후 이산화탄소 배양기에서 3시간 동안 배양한 후 위쪽 챔버를 분리하였다. 분리한 챔버 내에서 이동한 세포의 수를 Vi-Cell 세포 계수기를 이용하여 측정하였다. 그 결과는 도 2에 나타내었다. (P<0.001; ***, P<0.001; ###)Specifically, in this experiment, THP-1 cells were divided into 7 experimental groups and 27-hydroxycholesterol (27OH, manufactured by Santa Cruz Biotechnology) and 1 μg / ml of the compounds of Formulas 2 to 6 One was treated together and then cultured. In addition, one test group was cultured without any treatment as a negative control group, and the other test group was treated with only 27-hydroxycholesterol as a positive control group and then cultured. Cultivation was performed for 48 hours after drug treatment. After that, the medium and cells were separated by centrifugation, and the separated medium was dispensed into the lower chamber. On the other hand, 5 × 10 5 THP-1 cells contained in 100 μl of BSA (0.1%) were dispensed into the upper chamber of the transwell. After incubation for 3 hours in a CO2 incubator, the upper chamber was removed. The number of cells migrated in the separated chamber was measured using a Vi-Cell cell counter. The results are shown in Fig. (P <0.001; ***, P <0.001;###)
도 2에 나타낸 바와 같이, 양성 대조군에서는 27-하이드록시콜레스테롤 처리에 의하여 단핵구의 이동이 현저히 증가하였음을 확인하였다. 이 후 화학식 2 내지 5의 화합물을 처리한 경우에 단핵구의 이동이 현저하게 감소하여 음성 대조군의 경우와 유사한 수준 혹은 그보다 더 감소하는 것을 확인하였다. 다만, 화학식 6의 화합물을 처리한 경우에는 화학식 2 내지 5의 화합물을 처리한 경우와 달리 단핵구의 이동이 감소하지 않고, 단핵구의 이동성이 양성대조군과 비슷한 수준으로 유지됨을 확인하였다. 이는 본 발명의 레블라스타틴 유도체가 특이적으로 27-하이드록시콜레스테롤의 활성에 의한 단핵구 이동을 억제함을 나타낸다.As shown in FIG. 2, it was confirmed that the migration of mononuclear cells was significantly increased by treatment with 27-hydroxycholesterol in the positive control group. It was confirmed that the treatment of the compounds of the formulas (2) to (5) thereafter markedly decreased the migration of mononuclear cells and decreased to a level similar to or lower than that of the negative control group. However, when the compound of Chemical Formula 6 was treated, the mobility of monocytes was not decreased and the mobility of monocytes was maintained at a level similar to that of the positive control, unlike the case of treating the compounds of Chemical Formulas 2 to 5. This indicates that the levulastatin derivative of the present invention specifically inhibits mononuclear migration by the activity of 27-hydroxycholesterol.
실험예Experimental Example 3. 3. 유세포Flow cell 분석기를 이용한 Analyzer 레블라스타틴Levulastatin 유도체의 Derivative 죽상동맥경화증Atherosclerosis 관련 relation 면역인자Immune factor 발현 변화 분석 Analysis of expression changes
유세포 분석기인 FACS(Fluorescence activated cell sorter)를 이용하여 본 발명의 레블라스타틴 유도체의 죽상동맥경화증 억제 효과, 특히 죽상동맥경화증에 의해 발현되는 관련 면역인자인 CD105, CD137 및 CD166의 발현 변화를 확인하는 실험을 수행하였다. 본 발명에 사용한 THP-1 단핵구 세포(ATCCⓡTIB-202TM)는 ATCC(American Type Culture Collection)사로부터 구매하였으며, 함께 제공받은 메뉴얼에 따라 THP-1 세포를 배양하였다. Using FACS (Fluorescence activated cell sorter) as a flow cytometry analyzer, the effect of the levulastatin derivative of the present invention on the inhibition of atherosclerosis, in particular, the expression of CD105, CD137 and CD166, which are related immune factors expressed by atherosclerosis Experiments were performed. THP-1 monocyte cells (ATCC ⓡ TIB-202 TM ) used in the present invention were purchased from ATCC (American Type Culture Collection), and THP-1 cells were cultured according to the provided manual.
구체적으로, 본 실험은 THP-1 세포를 7개의 실험군으로 나눈 후 각각에 27-하이드록시콜레스테롤(27OH, Santa Cruz Biotechnology사)과 상기 실시예 1에서 제조한 1 μg/ml의 화학식 2 내지 6 중 어느 하나와 함께 처리한 후 배양하였다. 또한, 하나의 실험군은 음성대조군으로서 어떤 것도 처리하지 않고 배양만을 수행하였고, 나머지 하나의 실험군은 양성대조군으로서 27-하이드록시콜레스테롤만을 처리한 후 배양하였다. 배양은 약물 처리 후 48시간 동안 수행하였다. 이 후 상기 배양된 세포를 분리한 후 PBS로 세척하였다. 세척된 세포를 CD105, CD137 및 CD166에 대한 1차 항체액에 현탁한 후 그 상태로 4℃ 온도 조건 하에서 2시간 동안 그대로 두었다. 다시 PBS로 상기 세포들을 세척한 후 500μl의 파라포르말린(1%)에 세포를 현탁하였으며, 이 후 유세포분석기(FACS canto Ⅱ, BD사)로 각 세포를 분석하였다. CD105에 대하여 도출된 결과는 도 3a에 나타내고, CD137은 도 3b에, CD166은 도 3c에 나타내었다. 한편, 상기에 사용한 CD105, CD137 및 CD166에 대한 1차 항체는 각각 Santa cruz Biotechnology사에서 구매한 cat#:SC-20532, cat#:SC-367393 및 cat#:SC-25624를 사용하였다.Specifically, in this experiment, THP-1 cells were divided into 7 experimental groups and 27-hydroxycholesterol (27OH, manufactured by Santa Cruz Biotechnology) and 1 μg / ml of the compounds of Formulas 2 to 6 After treatment with either one, the cells were cultured. In addition, one test group was cultured without any treatment as a negative control group, and the other test group was treated with only 27-hydroxycholesterol as a positive control group and then cultured. Cultivation was performed for 48 hours after drug treatment. The cultured cells were then separated and washed with PBS. The washed cells were suspended in the primary antibody solution for CD105, CD137 and CD166, and left as such for 2 hours under the temperature condition of 4 占 폚. After washing the cells with PBS, the cells were suspended in 500 μl of paraformalin (1%). Then, each cell was analyzed with a flow cytometer (FACS canto II, BD). Results obtained for CD105 are shown in Fig. 3A, CD137 is shown in Fig. 3B, and CD166 is shown in Fig. 3C. On the other hand, cat #: SC-20532, cat #: SC-367393 and cat #: SC-25624 purchased from Santa Cruz Biotechnology were used as primary antibodies against CD105, CD137 and CD166.
도 3에 나타낸 바와 같이, 양성 대조군에서는 27-하이드록시콜레스테롤 처리에 의하여 CD105, CD137 및 CD166의 발현이 증가하였음을 확인하였고, 많게는 8배 이상 증가하였음을 확인하였다. 이 후 화학식 2 내지 5의 화합물을 처리한 경우에는 CD105, CD137 및 CD166의 발현이 현저하게 감소하여 음성 대조군의 경우와 유사한 수준으로 감소하는 것을 확인하였다. 다만, 화학식 6의 화합물을 처리한 경우에는 화학식 2 내지 5의 화합물을 처리한 경우와 달리 양성대조군과 같이 CD105, CD137 및 CD166의 발현이 여전히 높은 수준으로 유지됨을 확인하였다. 이는 본 발명의 레블라스타틴 유도체가 특이적으로 27-하이드록시콜레스테롤의 활성에 의한 CD105, CD137 및 CD166의 발현을 억제함을 나타낸다.As shown in FIG. 3, it was confirmed that the expression of CD105, CD137 and CD166 was increased by the treatment with 27-hydroxycholesterol in the positive control group, and it was confirmed that the expression was increased more than 8 times. The expression of CD105, CD137 and CD166 was markedly decreased in the case of treatment with the compounds of the formulas (2) to (5) and then decreased to a level similar to that of the negative control. However, when the compound of Chemical Formula 6 was treated, it was confirmed that the expression of CD105, CD137, and CD166 was still maintained at a high level as in the positive control, unlike the case of treating the compounds of Chemical Formulas 2 to 5. This shows that the levulastatin derivative of the present invention specifically inhibits the expression of CD105, CD137 and CD166 by the activity of 27-hydroxycholesterol.
종합적으로, 본 발명의 레블라스타틴 유도체 또는 이의 허용가능한 염은 죽상동맥경화증에 의하여 발현이 증가하는 27-하이드록시콜레스테롤에 의한 CCL2의 분비와 단핵구의 이동 및 관련 면역 인자의 발현을 억제하는 바, 죽상동맥경화증의 치료제, 건강기능식품, 치료 보조제 등으로 다양하게 활용될 수 있다는 이점이 있다. 더욱이 죽상동맥경화증의 심화로 인하여 발생될 수 있는 죽상동맥경화증에 의한 다양한 합병증의 예방 또는 치료 기능을 가지는 바, 죽상동맥경화증에 의한 합병증, 특히 허혈성 심장질환, 뇌졸중, 신부전 및 허혈성 사지질환의 치료제 및 건강기능식품 등으로 활용될 수 있다는 이점이 있다.In summary, the levulastatin derivatives or acceptable salts thereof of the present invention inhibit the secretion of CCL2, the migration of mononuclear cells and the expression of related immune factors by 27-hydroxycholesterol, which is increased in expression by atherosclerosis, A therapeutic agent for atherosclerosis, a health functional food, a therapeutic aid, and the like. Furthermore, it has a function of preventing or treating various complications due to atherosclerosis which may be caused by deepening of atherosclerosis, and it is a therapeutic agent for a complication caused by atherosclerosis, in particular ischemic heart disease, stroke, renal failure and ischemic limb disease It can be used as a functional food for health and the like.
이하 본 발명의 레블라스타틴 유도체 또는 이의 허용가능한 염을 포함하는 약학 조성물의 제제예를 설명하나, 본 발명을 한정하고자 함이 아니고 단지 이를 구체적으로 설명하고자 함이다.Hereinafter, formulation examples of the pharmaceutical composition including the levulastatin derivative of the present invention or an acceptable salt thereof will be described, but the present invention is not intended to be limited thereto but is specifically described.
제제예 1. 약학적 제제의 제조Formulation Example 1. Preparation of pharmaceutical preparations
1. 산제의 제조 1. Manufacturing of powder
레블라스타틴 유도체 또는 이의 허용가능한 염 20 mgThe levulastatin derivative or its acceptable salt 20 mg
유당 100 mgLactose 100 mg
탈크 10 mgTalc 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조할 수 있다.The above components can be mixed and filled in an airtight container to prepare powders.
2. 정제의 제조2. Preparation of tablets
레블라스타틴 유도체 또는 이의 허용가능한 염 10 mgThe levulastatin derivative or its acceptable salt 10 mg
옥수수전분 100 mgCorn starch 100 mg
유당 100 mgLactose 100 mg
스테아린산 마그네슘 2 mgMagnesium stearate 2 mg
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조할 수 있다.After mixing the above components, tablets may be prepared by tableting according to a conventional method for producing tablets.
3. 캡슐제의 제조3. Preparation of capsules
레블라스타틴 유도체 또는 이의 허용가능한 염 10 mgThe levulastatin derivative or its acceptable salt 10 mg
결정성 셀룰로오스 3 mgCrystalline cellulose 3 mg
락토오스 14.8 mgLactose 14.8 mg
마그네슘 스테아레이트 0.2 mgMagnesium stearate 0.2 mg
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조할 수 있다.The above components may be mixed and filled in a gelatin capsule according to a conventional method for preparing a capsule, thereby preparing a capsule.
4. 주사제의 제조4. Preparation of injections
레블라스타틴 유도체 또는 이의 허용가능한 염 10 mgThe levulastatin derivative or its acceptable salt 10 mg
만니톨 180 mg180 mg mannitol
주사용 멸균 증류수 2974 mgSterile sterilized water for injection 2974 mg
Na2HPO42H2O 26 mgNa 2 HPO 4 2H 2 O 26 mg
통상의 주사제의 제조방법에 따라 1 앰플당 (2 ml) 상기의 성분 함량으로 제조할 수 있다.(2 ml) per 1 ampoule according to the usual injection preparation method.
5. 액제의 제조5. Manufacture of liquids
레블라스타틴 유도체 또는 이의 허용가능한 염 20 mgThe levulastatin derivative or its acceptable salt 20 mg
이성화당 10 g10 g per isomer
만니톨 5 g5 g mannitol
정제수 적량Purified water quantity
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고, 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 다시 정제수를 가한다. 전체를 정제수로 가한 액제의 약을 전체 100 ml로 조절한 후 갈색병에 충진하여 멸균시켜 최종적으로 액제를 제조할 수 있다.Each component is added to and dissolved in purified water according to a conventional liquid preparation method, and the lemon flavor is added in an appropriate amount, then the above components are mixed, and then purified water is added. The total amount of the liquid agent added to the purified water is adjusted to 100 ml, and the liquid agent can be finally prepared by filling it in a brown bottle and sterilizing it.
Claims (9)
[화학식 2]
[화학식 3]
[화학식 4]
[화학식 5]
.A pharmaceutical composition for preventing or treating atherosclerosis comprising a compound represented by any one of the following formulas (2) to (5):
(2)
(3)
[Chemical Formula 4]
[Chemical Formula 5]
.
상기 죽상동맥경화증은 죽상 경화증 또는 동맥 경화증인 것을 특징으로 하는, 죽상동맥경화증 예방 또는 치료용 약학적 조성물.
3. The method of claim 2,
Wherein said atherosclerosis is atherosclerosis or arteriosclerosis. 2. A pharmaceutical composition for the prevention or treatment of atherosclerosis according to claim 1, wherein said atherosclerosis is atherosclerosis or atherosclerosis.
상기 조성물은 27-하이드록시콜레스테롤의 활성을 억제하는 것을 특징으로 하는, 죽상동맥경화증 예방 또는 치료용 약학적 조성물.
3. The method of claim 2,
The pharmaceutical composition for preventing or treating atherosclerosis, wherein the composition inhibits the activity of 27-hydroxycholesterol.
[화학식 2]
[화학식 3]
[화학식 4]
[화학식 5]
.
A health functional food composition for preventing or ameliorating atherosclerosis, comprising a levulastatin derivative represented by any one of the following formulas (2) to (5) or a pharmaceutically acceptable salt thereof:
(2)
(3)
[Chemical Formula 4]
[Chemical Formula 5]
.
[화학식 2]
[화학식 3]
[화학식 4]
[화학식 5]
.
A therapeutic agent for atherosclerosis comprising a levulastatin derivative represented by any one of the following formulas (2) to (5) or a pharmaceutically acceptable salt thereof:
(2)
(3)
[Chemical Formula 4]
[Chemical Formula 5]
.
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