KR102363895B1 - Pharmaceutical composition for the prevention or treatment of inflammatory diseases or immune disease - Google Patents
Pharmaceutical composition for the prevention or treatment of inflammatory diseases or immune disease Download PDFInfo
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- KR102363895B1 KR102363895B1 KR1020200026103A KR20200026103A KR102363895B1 KR 102363895 B1 KR102363895 B1 KR 102363895B1 KR 1020200026103 A KR1020200026103 A KR 1020200026103A KR 20200026103 A KR20200026103 A KR 20200026103A KR 102363895 B1 KR102363895 B1 KR 102363895B1
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- inflammatory
- disease
- pharmaceutical composition
- immune
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Abstract
본 발명은 염증 질환 또는 면역 질환의 예방, 개선 또는 치료를 위한 제제에 관한 것으로, 화학식 1로 표시되는 화합물이 염증 반응 및 면역 반응을 유도하는 헬퍼 T 세포의 분화를 억제하고, 염증 반응 및 면역 반응을 억제하는 조절 T 세포의 분화를 촉진함으로써, 염증 반응 및 면역 반응을 조절하는 활성이 있다는 것을 세포 및 동물 실험으로 확인함으로써, 이를 유효성분으로 포함하는 염증 질환 또는 면역 질환의 예방, 개선 또는 치료용 조성물을 제공한다.The present invention relates to an agent for the prevention, improvement or treatment of an inflammatory disease or an immune disease, wherein the compound represented by Formula 1 inhibits the differentiation of helper T cells that induce inflammatory and immune responses, and inflammatory and immune responses By promoting the differentiation of regulatory T cells that inhibit the inflammatory response and immune response by confirming that there is an activity to control the inflammatory response and immune response in cell and animal experiments, for the prevention, improvement or treatment of inflammatory diseases or immune diseases containing it as an active ingredient A composition is provided.
Description
본 발명은 염증 질환 또는 면역 질환의 예방, 개선 또는 치료를 위한 제제에 관한 것이다.The present invention relates to an agent for preventing, ameliorating or treating an inflammatory disease or an immune disease.
박테리아, 곰팡이, 바이러스, 다양한 종류의 알레르기 유발물질과 같은 외부 감염원이 인체에 침입하게 되며, 인체는 이들의 침입을 방지하기 위해 염증 또는 면역과 같은 방어 반응을 유도한다. 구체적으로, 외부 세균이 특정 조직에 침입하여 증식을 하게 되면 생체의 백혈구가 이를 인지하여 증식된 외부 세균을 활발히 공격하게 되는데, 이 과정 중 발생되는 백혈구의 사해가 균에 의하여 침입 받은 조직에 축적됨과 동시에 백혈구에 의하여 사멸된 침입균의 세포 파괴물이 침입 받은 조직 내로 융해되어 농양이 형성된다. 염증에 의한 농양의 치료는 소염작용을 통하여 촉진될 수 있는데, 소염작용이란 항균제를 이용하여 침입균의 증식을 억제하거나 농양중에 축적된 이물질들을 탐식하는 대식세포(macrophage)를 활성화하여 상기 이물질들을 소화 및 배설하는 대식세포의 기능을 항진시키는 등의 염증치료 촉진작용이다.External infectious agents such as bacteria, fungi, viruses, and various types of allergens invade the human body, and the human body induces a defense response such as inflammation or immunity to prevent the invasion. Specifically, when external bacteria invade and proliferate in a specific tissue, leukocytes in the living body recognize this and actively attack the proliferated external bacteria. At the same time, the cell debris of the invading bacteria killed by the white blood cells melts into the invaded tissue to form an abscess. The treatment of an abscess caused by inflammation can be promoted through anti-inflammatory action, which means using an antibacterial agent to suppress the growth of invading bacteria or to activate macrophages that phagocytose the foreign substances accumulated during the abscess to digest the foreign substances. and promoting the treatment of inflammation, such as enhancing the function of excreted macrophages.
일반적으로 이러한 방어 반응은 생체의 세포나 조직에 기질적 변화를 가져오는 침습으로 인한 손상을 수복 및 재생하기 위한 생체방어 반응과정이고, 이 반응과정에는 국소의 혈관, 체액의 각종 조직세포 및 면역세포 등이 작용한다. 정상적으로 외부 침입균에 의하여 유도되는 방어 반응은 생체를 보호하기 위한 방어 시스템인 반면, 비정상적으로 과도한 방어 반응이 유도되면 다양한 질환들이 나타나게 되는데, 이러한 질환들이 염증 질환 또는 면역 질환이다. 외부자극에 의하여 활성화된 표적세포로부터 분비되는 다양한 염증 매개물질이 염증을 증폭 및 지속시켜 인체의 생명을 위협하는 질환으로서 급성염증, 류마티스 관절염과 같은 관절내에서의 질환, 건선 등의 형태로 나타나는 피부질환 및 기관지 천식 등의 질환 등을 포함한다.In general, such a defense reaction is a biological defense reaction process for repairing and regenerating damage caused by invasion that causes organic changes in cells or tissues of the living body, and this reaction process includes local blood vessels, various tissue cells of body fluids, and immune cells etc works. The defense response normally induced by the external invading bacteria is a defense system to protect the living body, whereas when an abnormally excessive defense response is induced, various diseases appear, and these diseases are inflammatory diseases or immune diseases. Various inflammatory mediators secreted from target cells activated by external stimuli amplify and sustain inflammation, which is a disease that threatens the life of the human body. The skin appears in the form of acute inflammation, intra-articular diseases such as rheumatoid arthritis, and psoriasis. diseases and diseases such as bronchial asthma.
특히, 염증성 장질환(Inflammatory bowel disease, IBD)은 임상적으로 유사하면서도, 조직학적 소견과 내시경 및 면역학적 측면에서 서로 다른 궤양성 대장염 및 크론병의 두 가지 질환으로 분류된다. 이러한 IBD는 염증세포의 활성화가 중요한 병인인 것으로 알려져 있다. 장면역계의 지속적이거나 부적절한 활성화는 만성 점막성 염증의 병리생리에 중요한 역할을 하며, 특히 호중구, 대식세포, 림프구 및 비만세포의 침윤에 의해 결국 점막 파괴 및 궤양을 초래한다. 침윤되고 활성화된 호중구는 활성산소종의 중요한 원인이 되며, 이러한 활성종은 세포독성 물질로서 가교 단백질, 지질 및 핵산에 의해 세포성 산화 스트레스를 유도하고 상피성 기능장애 및 손상을 초래한다.In particular, inflammatory bowel disease (IBD) is classified into two diseases, ulcerative colitis and Crohn's disease, which are clinically similar, but differ from each other in histological, endoscopic, and immunological aspects. It is known that activation of inflammatory cells is an important etiology of IBD. Persistent or inappropriate activation of the intestinal system plays an important role in the pathophysiology of chronic mucosal inflammation, and in particular, infiltration of neutrophils, macrophages, lymphocytes and mast cells results in mucosal destruction and ulceration. Infiltrating and activated neutrophils are an important cause of reactive oxygen species, which induce cellular oxidative stress by cross-linking proteins, lipids and nucleic acids as cytotoxic substances and cause epithelial dysfunction and damage.
염증성 장질환이 있으면 장관의 점막에서 다양한 염증성 사이토카인들이 분비된다. TNF-α는 궤양성 대장염 환자의 대장 루멘과 대장 상피세포에서 높게 나타난다. 최근 연구에 의하면, TNF-α는 궤양성 대장염의 병인으로 중요한 역할을 한다고 알려졌다. 항-TNF-α 항체인 인플릭시맵(infliximab)은 종기의 치료뿐 아니라, 기존에 치료되지 않던 크론병의 치료에 효과적이라고 알려졌다. 그러나, 이러한 치료법은 비용이 많이 들고, 일부 환자에게서는 수액 반응 또는 전염성 합병증과 같은 부작용이 야기된다.In inflammatory bowel disease, various inflammatory cytokines are secreted from the intestinal mucosa. TNF-α is highly expressed in colonic lumen and colonic epithelial cells of ulcerative colitis patients. According to a recent study, TNF-α is known to play an important role in the pathogenesis of ulcerative colitis. Infliximab, an anti-TNF-α antibody, is known to be effective not only for the treatment of boils, but also for the treatment of previously untreated Crohn's disease. However, these treatments are expensive and cause side effects such as fluid reactions or infectious complications in some patients.
또한, IBD를 지닌 환자의 점막에서는 유의성 있게 인터루킨-8(IL-8)이 상승하고, 모세혈관 신생을 촉진하는 것으로 알려져 있다. 대장에서의 염증이 심할수록 IL-8의 발현이 증가하며, 설치류를 이용한 동물실험 모델에서 IL-8 특이적 항체가 장염증을 감소시킨다는 것이 알려졌다. 이때, 세포내 Ca2+의 변화가 IL-8 유도의 중요한 요소로 작용한다.In addition, it is known that interleukin-8 (IL-8) significantly increases in the mucous membrane of patients with IBD and promotes capillary angiogenesis. The more severe the inflammation in the colon, the higher the expression of IL-8, and it was known that IL-8-specific antibodies reduce intestinal inflammation in an animal model using rodents. At this time, changes in intracellular Ca 2+ act as an important factor in IL-8 induction.
현재 염증성 장질환 치료제로는 프로스타글란딘(prostaglandins)의 생성을 차단하는 5-아미노살리실산(5-aminosalicylic acid; 5-ASA) 계통 약물 예를 들어, 설파살라진 등을 이용하거나, 스테로이드류의 면역억제제를 사용하고 있다. 설파살라진은 복부허실(fullness), 두통, 발진, 간질환, 백혈구 감소증, 무과립구증, 남성 불임 등과 같은 부작용 또는 역효과를 일으키기 쉽다. 또한, 설파살라진이 장의 환부를 절개한 환자 또는 차도가 있는 환자에게 충분한 재발 억제 효과가 있는지는 불분명하다.Currently, as a treatment for inflammatory bowel disease, a 5-aminosalicylic acid (5-ASA)-based drug that blocks the production of prostaglandins, such as sulfasalazine, is used, or an immunosuppressant of steroids is used. there is. Sulfasalazine is prone to side effects or adverse effects such as abdominal fullness, headache, rash, liver disease, leukopenia, agranulocytosis, and male infertility. In addition, it is unclear whether sulfasalazine has sufficient relapse inhibitory effect in patients with intestinal incision or in patients with remission.
스테로이드류의 면역억제제는 부신피질 스테로이드로서, 단기적인 효과는 인정받고 있지만, 장기적인 예후를 향상시킬 수는 없다. 또한, 유도된 감염성 질환, 2차 부신피질 부전증, 소화성 궤양, 당뇨병, 정신장애, 스테로이드성 신장병 등과 같은 부작용의 측면에서 단지 급성인 경우에만 사용되어야 하는 한계가 있다. 즉, 아직까지 염증성 장질환에 대해 신뢰할 만한 경구용 치료요법이 없으므로, 이러한 질환에 대해 효과적이고 저비용의 경구용인 치료제의 개발이 요구되고 있다.Steroid immunosuppressants are adrenocortical steroids, and although short-term effects are recognized, they cannot improve long-term prognosis. In addition, in terms of side effects such as induced infectious disease, secondary adrenocortical insufficiency, peptic ulcer, diabetes, psychiatric disorder, steroidal nephropathy, etc., there is a limitation in that it should be used only in acute cases. That is, since there is still no reliable oral therapy for inflammatory bowel disease, the development of an effective and low-cost oral therapeutic agent for these diseases is required.
한편, 각종 병원체에 대한 생체 방어 시스템인 면역계에서 중심적 역할을 담당하는 세포군의 하나로 T 세포가 있다. T 세포는 인체의 흉선에서 생성되며, 일련의 분화 과정을 거치면서 고유의 특성을 지닌 T 세포로 분화한다. 분화를 완료한 T 세포는 그 기능에 따라 크게 CD8 T 세포 및 CD4 T 세포로 구분된다. 이 중 CD4 T 세포는 환경적인 요인에 따라 세부적으로 분화가 되는데, 가장 대표적인 것이 헬퍼 T 세포 및 조절 T 세포이다.Meanwhile, T cells are one of the cell groups that play a central role in the immune system, which is a biological defense system against various pathogens. T cells are generated in the thymus of the human body, and through a series of differentiation processes, they differentiate into T cells with unique characteristics. T cells that have completed differentiation are largely divided into CD8 T cells and CD4 T cells according to their functions. Among them, CD4 T cells are differentiated in detail according to environmental factors, and the most representative ones are helper T cells and regulatory T cells.
최근, 헬퍼 T 세포인 Th1 세포와 Th17 세포에 의한 자가면역 질환 연구 결과에 따르면, 이들 세포의 활성을 조절할 수 있는 조절 T 세포(Treg)의 기능의 기작이 알려지면서 이를 이용한 면역질환의 치료에 대한 연구가 대두되고 있다. Treg 세포는 비정상적으로 활성화된 면역세포의 기능을 억제하여 염증 반응을 제어하는 특성을 가진다. Treg 세포의 활성을 증가시키는 작용을 통해 면역질환을 치료하는 실험들이 많이 보고되고 있다. Th1 세포 및 Th17 세포는 면역질환에서 보이는 염증반응의 최전방에서 관여하여 염증 반응의 신호를 최대화하여 질병의 진행을 가속화 시키는 것이 밝혀지고 있다. 그러므로, 자가면역 질환 중 Treg 세포에 의해 제어되지 않는 자가면역 질환의 경우, Th1 및 Th17 세포 활성의 억제를 표적으로 한 자가면역 질환의 치료제 개발이 크게 부각되고 있다.Recently, according to the results of studies on autoimmune diseases by helper T cells, Th1 cells and Th17 cells, the mechanism of the function of regulatory T cells (Tregs) that can regulate the activity of these cells is known, and the treatment of immune diseases using them is known. Research is on the rise. Treg cells have the property of controlling the inflammatory response by suppressing the function of abnormally activated immune cells. Many experiments have been reported to treat immune diseases through the action of increasing the activity of Treg cells. It has been found that Th1 cells and Th17 cells are involved in the forefront of the inflammatory response seen in immune diseases, thereby maximizing the signal of the inflammatory response and accelerating the disease progression. Therefore, in the case of autoimmune diseases that are not controlled by Treg cells among autoimmune diseases, the development of therapeutic agents for autoimmune diseases targeting the inhibition of Th1 and Th17 cell activity has been highlighted.
현재 사용되고 있는 면역질환 치료제로는 T 세포에서의 신호변환 경로를 차단하는 면역 억제제가 가장 많이 사용되고 있는데, 이러한 면역억제제들은 독성, 감염, 임파종, 당뇨병, 진전(tremor), 두통, 설사, 고혈압, 오심 또는 신기능 장애 등의 부작용이 발생하는 문제점이 있다.Currently used immunosuppressants that block the signal transduction pathway in T cells are the most used immunosuppressants currently used for the treatment of immune diseases. Or there is a problem that side effects such as renal dysfunction occurs.
또한, T 세포의 활성화를 억제하는 방법을 통해 면역질환을 치료하는 방법 이외에도, 면역 세포로부터 분비되는 사이토카인의 양을 조절하는 치료법, 및 면역 세포로부터 분비되는 사이토카인을 표적으로 하는 항체를 이용한 치료법이 개발 중에 있다. 그러나 이러한 방법은 실제적으로 임상실험을 거쳐 환자들에게 적용하기까지 많은 시간이 소요되어야 한다. 또한 항체를 이용하는 방법은 항체 제작 과정에서 너무 많은 비용이 든다는 문제점이 있다. 따라서 부작용이 없고 저렴하면서도 치료 효과가 우수한 새로운 면역질환 치료제의 개발이 필요한 실정이다.In addition, in addition to a method of treating immune diseases through a method of inhibiting T cell activation, a treatment method that controls the amount of cytokines secreted from immune cells, and a treatment method using an antibody targeting cytokines secreted from immune cells This is under development. However, this method must take a lot of time before it is applied to patients through clinical trials. In addition, the method using the antibody has a problem in that it costs too much in the antibody production process. Therefore, there is a need to develop a new therapeutic agent for immune diseases that has no side effects, is inexpensive, and has excellent therapeutic effects.
본 발명자들은 이와 같은 점을 감안하여 대사 산물 중에서 일부 화합물이 염증 반응 또는 면역 반응을 조절하는 효과를 세포 및 동물 모델에서 확인함으로써 본 발명을 완성하였다.The present inventors have completed the present invention by confirming the effect of some of the metabolites on regulating an inflammatory response or an immune response in cell and animal models in consideration of this point.
본 발명은 염증 질환 또는 면역 질환의 예방, 개선 또는 치료를 위한 제제에 관한 것으로, 본 발명에 따른 화학식 1로 표시되는 화합물이 염증 반응 및 면역 반응을 유도하는 헬퍼 T 세포의 분화를 억제하고, 염증 반응 및 면역 반응을 억제하는 조절 T 세포의 분화를 촉진함으로써, 염증 반응 및 면역 반응을 조절하는 활성이 있다는 것을 세포 및 동물 실험으로 확인함으로써, 이를 유효성분으로 포함하는 염증 질환 또는 면역 질환의 예방, 개선 또는 치료용 조성물을 제공하는 것이다.The present invention relates to an agent for the prevention, improvement or treatment of an inflammatory disease or an immune disease, wherein the compound represented by Formula 1 according to the present invention inhibits the differentiation of helper T cells that induce an inflammatory response and an immune response, By promoting the differentiation of regulatory T cells that suppress the reaction and immune response, by confirming that there is an activity to regulate the inflammatory response and the immune response by cell and animal experiments, prevention of inflammatory diseases or immune diseases containing it as an active ingredient, It is to provide a composition for improvement or treatment.
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 염증 질환 또는 면역 질환의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease or an immune disease comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Formula 1]
상기 n은 1-3의 정수이고, R은 수소 또는 P2O6 3- 중에서 선택되며, 상기 점선을 포함한 결합은 단일결합 또는 이중결합을 나타낸다.Wherein n is an integer of 1-3, R is selected from hydrogen or P 2 O 6 3- , and the bond including the dotted line represents a single bond or a double bond.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 염증 질환 또는 면역 질환의 예방 또는 개선용 건강기능 식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for the prevention or improvement of inflammatory diseases or immune diseases comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에 따르면, 화학식 1로 표시되는 화합물이 염증 반응 및 면역 반응을 유도하는 헬퍼 T 세포의 분화를 억제하고, 염증 반응 및 면역 반응을 억제하는 조절 T 세포의 분화를 촉진함으로써, 염증 반응 및 면역 반응을 조절하는 활성이 있다는 것을 세포 및 동물 실험으로 확인함으로써, 이를 유효성분으로 포함하는 염증 질환 또는 면역 질환의 예방, 개선 또는 치료용 조성물로 제공될 수 있다.According to the present invention, the compound represented by Formula 1 suppresses the differentiation of helper T cells that induce inflammatory and immune responses, and promotes the differentiation of regulatory T cells that suppress inflammatory and immune responses, thereby inflammatory and immune responses. It can be provided as a composition for preventing, improving, or treating an inflammatory disease or an immune disease comprising it as an active ingredient by confirming that there is an activity to modulate the response through cell and animal experiments.
도 1은 본 발명에 따른 화합물에 의한 헬퍼 T 세포 및 조절 T 세포의 in vitro 분화에 미치는 영향을 평가한 그래프이다. A는 Th1 세포의 분화 퍼센트이고, B는 Th17 세포의 분화 퍼센트이고, C 및 D는 조절 T 세포의 분화 퍼센트이다. RA는 유사 대조군으로 사용되었다.
도 2는 CD4+ 세포에서 본 발명에 따른 화합물의 농도에 따른 세포 독성 평가를 확인한 결과이다.
도 3은 동물 모델에서 본 발명에 따른 화합물의 투여에 따른 체중 및 혈변 횟수에 미치는 영향을 평가한 그래프이다.
도 4는 동물 모델에서 본 발명에 따른 화합물의 투여에 따른 헬퍼 T 세포 및 조절 T 세포의 수 변화를 평가한 그래프이다.1 is a graph evaluating the effect of a compound according to the present invention on the in vitro differentiation of helper T cells and regulatory T cells. A is the percent differentiation of Th1 cells, B is the percent differentiation of Th17 cells, and C and D are the percent differentiation of regulatory T cells. RA was used as a similar control.
2 is a result of confirming the evaluation of cytotoxicity according to the concentration of the compound according to the present invention in CD4 + cells.
3 is a graph evaluating the effect of administration of a compound according to the present invention on body weight and number of bloody stools in an animal model.
4 is a graph evaluating the change in the number of helper T cells and regulatory T cells according to the administration of the compound according to the present invention in an animal model.
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 as currently widely used general terms as possible while considering the functions in the present invention, but these may vary depending on the intention or precedent of a person skilled in the art, the emergence of new technology, and the like. In addition, in a specific case, there is a term arbitrarily selected by the applicant, and in this case, the meaning will be described in detail in the description of the corresponding 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, rather than the name of a simple 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 and scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Terms such as those defined in a commonly used dictionary should be interpreted as having a meaning consistent with the meaning in the context of the related art, and should not be interpreted in an ideal or excessively formal meaning unless explicitly defined in the present application. does not
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 in that range. Every maximum numerical limitation given throughout this specification includes all lower numerical limitations as if the lower numerical limitation were expressly written. Every minimum numerical limitation given throughout this specification includes all higher numerical limitations as if the higher numerical limitation were expressly written. Any numerical limitation given throughout this specification shall include all numerical ranges within the broader numerical range, as if the narrower numerical limitation were expressly written down.
이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 염증 질환 또는 면역 질환의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease or an immune disease comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Formula 1]
상기 n은 1-3의 정수이고, R은 수소 또는 P2O6 3- 중에서 선택되며, 상기 점선을 포함한 결합은 단일결합 또는 이중결합을 나타낸다.Wherein n is an integer of 1-3, R is selected from hydrogen or P 2 O 6 3- , and the bond including the dotted line represents a single bond or a double bond.
상기 화합물 또는 이의 약학적으로 허용 가능한 염은 제라닐제라닐 피로포스페이트염(geranylgeranyl pyrophosphate salt), 파네실 피로포스페이트염(farnesyl pyrophosphate salt), 제라닐제라니올(geranylgeraniol), 파네솔(farnesol) 및 피톨(phytol)로 이루어진 군에서 선택된 어느 하나일 수 있다.The compound or a pharmaceutically acceptable salt thereof is geranylgeranyl pyrophosphate salt, farnesyl pyrophosphate salt, geranylgeraniol, farnesol and phytol. (phytol) may be any one selected from the group consisting of.
구체적으로 상기 화학식 1로 표시되는 화합물은 GGPP(geranylgeranyl pyrophosphate)일 수 있으며, GGPP는 제라닐제라닐 피로인산 또는 제라닐제라닐 2인산염(geranylgeranyl diphosphate)이라고 불릴 수 있다.Specifically, the compound represented by
상기 화합물은 다이테르펜 및 다이테르페노이드의 생합성 과정에서의 대사 중간생성물이며, 카로티노이드, 지베렐린, 토코페롤 및 엽록소의 전구물질이기도 하다. 화합물은 사람의 세포에서 중요하게 사용되는 제라닐제라닐화된 단백질의 전구물질이며, 중간창자의 상피세포를 가로질러 생식세포를 이동시키는 화학유인물질로 이용된다. 유인신호는 생식샘 전구세포에서 생산되어 생식세포를 이들 부위로 유도하여, 난자와 정자로 분화되도록 한다.These compounds are metabolic intermediates in the biosynthesis of diterpenes and diterpenoids, and are also precursors of carotenoids, gibberellins, tocopherols and chlorophyll. The compound is a precursor of geranylgeranylated protein, which is used importantly in human cells, and is used as a chemoattractant to migrate germ cells across the epithelial cells of the midgut. Attraction signals are produced by gonad progenitors to induce germ cells to these sites, allowing them to differentiate into eggs and sperm.
상기 염증 질환은 염증성 장질환, 피부염, 알레르기, 아토피, 결막염, 치주염, 비염, 중이염, 인후염, 편도염, 폐렴, 위궤양, 위염, 크론병, 대장염, 강직성 척추염, 건선관절염, 골관절염, 류마티스 관절염, 견관절주위염, 건염, 건초염, 건주위염, 근육염, 간염, 방광염, 신장염, 또는 쇼그렌 증후군(sjogren's syndrome)일 수 있으나, 이에 제한되는 것은 아니다.The inflammatory disease is inflammatory bowel disease, dermatitis, allergy, atopic dermatitis, conjunctivitis, periodontitis, rhinitis, otitis media, pharyngitis, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, ankylosing spondylitis, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, periarthritis , tendinitis, tendinitis, peritenitis, myositis, hepatitis, cystitis, nephritis, or Sjogren's syndrome, but is not limited thereto.
상기 면역 질환은 자가면역질환, 이식거부, 또는 이식편대숙주병일 수 있으며, 상기 자가면역질환은 다발성 경화증, 크론씨병, 홍반병, 아토피, 하시모토 갑상선염, 악성빈혈, 에디슨씨 병, 제1형 당뇨, 루프스, 만성피로증후군, 섬유근육통, 갑상선기능저하증과 항진증, 경피증, 베체트병, 염증성 장질환, 중증 근무력증, 메니에르 증후군(Meniere's syndrome), 길리안-바레 증후근(Guilian-Barre syndrome), 쇼그렌 증후군(Sjogren's syndrome), 백반증, 자궁내막증, 건선, 백반증, 전신성 경피증, 천식 또는 궤양성 대장염일 수 있으나, 이에 제한되는 것은 아니다.The immune disease may be an autoimmune disease, transplant rejection, or graft-versus-host disease, and the autoimmune disease is multiple sclerosis, Crohn's disease, erythematosus, atopy, Hashimoto's thyroiditis, pernicious anemia, Addison's disease,
상기 화합물은 헬퍼 T 세포인 Th1 세포 및 Th17 세포의 분화를 억제하여 염증 반응 또는 면역 반응을 억제할 수 있고, 조절 T 세포의 분화를 촉진하여 염증 반응 또는 면역 반응을 억제할 수 있다.The compound may suppress the inflammatory or immune response by inhibiting the differentiation of Th1 cells and Th17 cells, which are helper T cells, and may suppress the inflammatory or immune response by promoting the differentiation of regulatory T cells.
Th1 세포는 세포 매개성 면역에 관여하고, Th17 세포는 감염 및 염증 질환에 관여하고, 조절 T 세포는 면역을 억제하여 항상성을 유지하게 만들어 준다. 면역계에서 이러한 세포 집단들은 서로 과활성화되지 않도록 서로 견제를 통해 면역계의 균형을 유지하고 있다. 면역질환의 대부분은 이러한 면역 세포 간의 불균형에 기인하는 것으로 볼 수 있다. 예를 들어, Th1 세포와 Th17 세포의 활성이 비정상적으로 증가하는 경우 자가면역 질환이 발생하는 것으로 알려져 있다.Th1 cells are involved in cell-mediated immunity, Th17 cells are involved in infectious and inflammatory diseases, and regulatory T cells are responsible for maintaining homeostasis by suppressing immunity. In the immune system, these cell populations maintain the balance of the immune system by checking each other so that they do not overactivate each other. Most of the immune diseases can be attributed to the imbalance between these immune cells. For example, it is known that an autoimmune disease occurs when the activities of Th1 cells and Th17 cells are abnormally increased.
상기 약학적 조성물은 약학 조성물의 제조에 통상적으로 사용되는 적절한 담체, 부형제 또는 희석제를 추가로 포함할 수 있다.The pharmaceutical composition may further include an appropriate carrier, excipient or diluent commonly used in the preparation of pharmaceutical compositions.
상기 약학적 조성물은 크림, 젤, 패취, 분무제, 연고제, 경고제, 로션제, 리니멘트제, 파스타제 및 카타플라스마제로 이루어진 군으로부터 선택되는 하나 이상의 외용제 형태로 제형화될 수 있다.The pharmaceutical composition may be formulated in the form of one or more external preparations selected from the group consisting of creams, gels, patches, sprays, ointments, warning agents, lotions, liniments, pastas, and cataplasmas.
본 발명의 약학적 조성물은 제형화를 위해 추가로 있는 약학적으로 허용가능한 담체 및 희석제를 포함할 수 있다. 상기 약학적으로 허용가능한 담체 및 희석제는 전분, 당, 및 만니톨과 같은 부형제, 칼슘 포스페이트 등과 같은 충전제 및 증량제, 카르복시메틸셀룰로오스, 히드록시프로필셀룰로오스 등과 같은 셀룰로오스 유도체, 젤라틴, 알긴산염, 및 폴리비닐 피롤리돈 등과 같은 결합제, 활석, 스테아린산 칼슘, 수소화 피마자유 및 폴리에틸렌 글리콜과 같은 윤활제, 포비돈, 크로스포비돈과 같은 붕해제, 폴리소르베이트, 세틸알코올, 및 글리세롤 등과 같은 계면활성제를 포함하나, 이에 한정되지 않는다. 상기 약학적으로 허용가능한 담체 및 희석제는 대상체에게 생물학적 및 생리학적으로 친화적인 것일 수 있다. 희석제의 예로는 염수, 수용성 완충액, 용매 및/또는 분산제(dispersion media)를 들 수 있으나, 이에 제한되는 것은 아니다.The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier and diluent for formulation. The pharmaceutically acceptable carriers and diluents include starch, sugar, and excipients such as mannitol, fillers and extenders such as calcium phosphate, cellulose derivatives such as carboxymethyl cellulose, hydroxypropyl cellulose, gelatin, alginate, and polyvinyl blood binders such as rolidone, lubricants such as talc, calcium stearate, hydrogenated castor oil and polyethylene glycol, disintegrants such as povidone, crospovidone, and surfactants such as polysorbates, cetyl alcohol, and glycerol does not The pharmaceutically acceptable carrier and diluent may be biologically and physiologically compatible with the subject. Examples of diluents include, but are not limited to, saline, aqueous buffers, solvents, and/or dispersion media.
본 발명의 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구 투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 바람직하게는 경구 투여된다. 또한 본 발명의 약학적 조성물의 투여량은 대상체의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도 등에 따라 그 범위가 다양하나, 이에 제한되는 것은 아니다.The pharmaceutical composition of the present invention may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically) according to a desired method, and is preferably administered orally. In addition, the dosage of the pharmaceutical composition of the present invention varies depending on the subject's body weight, age, sex, health status, diet, administration time, administration method, excretion rate and severity of disease, but is not limited thereto.
또한, 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 염증 질환 또는 면역 질환의 예방 또는 개선용 건강기능 식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for the prevention or improvement of inflammatory diseases or immune diseases comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Formula 1]
상기 n은 1-3의 정수이고, R은 수소 또는 P2O6 3- 중에서 선택되며, 상기 점선을 포함한 결합은 단일결합 또는 이중결합을 나타낸다.Wherein n is an integer of 1-3, R is selected from hydrogen or P 2 O 6 3- , and the bond including the dotted line represents a single bond or a double bond.
본 발명은 통상적으로 이용되는 식품으로써 일반적으로 사용될 수 있다.The present invention can be generally used as a commonly used food product.
본 발명의 식품 조성물은 건강기능식품으로서 사용될 수 있다. 상기 "건강기능 식품"이라 함은 건강기능 식품에 관한 법률에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, "기능성"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.The food composition of the present invention can be used as a health functional food. The term "health functional food" means a food manufactured and processed using raw materials or ingredients useful for the human body in accordance with the Health Functional Food Act, and "functionality" refers to the structure and function of the human body. It refers to ingestion for the purpose of obtaining useful effects for health purposes such as regulating nutrients or physiological effects.
본 발명의 식품 조성물은 통상의 식품 첨가물을 포함할 수 있으며, 상기 "식품 첨가물"로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전처에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.The food composition of the present invention may contain conventional food additives, and the suitability as the "food additive" is determined according to the general rules and general test methods of food additives approved by the Ministry of Food and Drug Safety, unless otherwise specified. It is judged according to the standards and standards related to the item.
상기 "식품 첨가물 공전"에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성물, 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물, L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류들을 들 수 있다.The items listed in the "Food Additives Code" include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; Mixed preparations such as sodium L-glutamate preparation, noodle-added alkali agent, preservative agent, and tar color agent can be mentioned.
본 발명의 식품 조성물은 질환의 예방 및/또는 개선을 목적으로, 정제, 캡슐, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공할 수 있다.The food composition of the present invention may be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. for the purpose of preventing and/or improving diseases.
예를 들어, 캡슐 형태의 건강기능 식품 중 경질캡슐제는 통상의 경질캡슐에 본 발명에 따른 조성물을 부형제 등의 첨가제와 혼합 및 충진하여 제조할 수 있으며, 연질캡슐제는 본 발명에 따른 조성물은 부형제 등의 첨가제와 혼합하고 젤라틴 등 캡슐기제에 충진하여 제조할 수 있다. 상기 연질캡슐제는 필요에 따라 글리세린 또는 소르비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다.For example, among health functional foods in the form of capsules, hard capsules can be prepared by mixing and filling a conventional hard capsule with the composition according to the present invention with additives such as excipients, and the soft capsule is a composition according to the present invention It can be manufactured by mixing with additives such as excipients and filling in capsule bases such as gelatin. The soft capsule formulation may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, if necessary.
상기 부형제, 결합제, 붕해제, 활택제, 교미제, 착향제 등에 대한 용어 정의는 당업계에 공지된 문헌에 기재된 것으로 그 기능 등이 동일 내지 유사한 것들을 포함한다. 상기 식품의 종류에는 특별한 제한이 없으며, 통상적인 의미에서의 건강기능식품을 모두 포함한다.The term definitions for the excipients, binders, disintegrants, lubricants, flavoring agents, and the like are described in documents known in the art and include those having the same or similar functions. The type of food is not particularly limited, and includes all health functional foods in the ordinary sense.
본 발명에서 용어 “예방”이란 본 발명에 따른 조성물의 투여로 질환의 억제 또는 지연시키는 모든 행위를 말한다. 본 발명에서 용어 “치료”는 본 발명에 따른 조성물의 투여로 질환의 증세가 호전되거나 이롭게 변경하는 모든 행위를 말한다. 본 발명에서 "개선"이란 본 발명의 조성물을 개체에 투여하거나 섭취시켜 질환의 나쁜 상태를 좋게 하는 모든 행위를 의미한다.In the present invention, the term “prevention” refers to any act of inhibiting or delaying a disease by administering the composition according to the present invention. In the present invention, the term “treatment” refers to any action that improves or beneficially changes the symptoms of a disease by administration of the composition according to the present invention. In the present invention, "improvement" refers to any action that improves the bad state of a disease by administering or ingesting the composition of the present invention to an individual.
상기 약학적 조성물은 항히스타민제, 소염진통제, 항암제 및 항생제로 이루어진 군에서 선택된 하나 이상의 약제와 함께 제제화하거나 병용하여 사용할 수 있다.The pharmaceutical composition may be formulated or used in combination with one or more drugs selected from the group consisting of antihistamines, anti-inflammatory analgesics, anticancer drugs, and antibiotics.
이하, 본 발명의 이해를 돕기 위하여 실험예 및 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실험예 및 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실험예 및 실시예에 한정되는 것은 아니다. 본 발명의 실험예 및 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, in order to help the understanding of the present invention, experimental examples and examples will be described in detail. However, the following experimental examples and examples are only to illustrate the content of the present invention, the scope of the present invention is not limited to the following experimental examples and examples. Experimental examples and examples of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.
이하, 실시예 등에서 사용한 시약은 시중에서 구할 수 있는 것으로, 최상품을 사용하였으며, 별도의 언급이 없는 한, Sigma-aldrich사에서 구입한 것을 사용하였다.Hereinafter, reagents used in Examples and the like were commercially available, and the best products were used, and unless otherwise stated, those purchased from Sigma-aldrich were used.
실시예 1. 본 발명에 따른 화합물의 헬퍼 T 세포 및 조절 T 세포의 분화 억제 효과Example 1. Effect of the compound according to the present invention in inhibiting differentiation of helper T cells and regulatory T cells
본 발명에 따른 본 발명에 따른 화합물이 염증 반응 및 면역 반응에 영향을 주는 면역세포에 미치는 영향을 평가하기 위해, 동물 모델로부터 염증성 면역 세포인 헬퍼 T 세포 및 조절 T 세포를 분리하였다.In order to evaluate the effect of the compound according to the present invention on the inflammatory response and immune cells affecting the immune response, helper T cells and regulatory T cells, which are inflammatory immune cells, were isolated from animal models.
B57BL/6 마우스의 비장(spleen)으로부터 CD4 마이크로비드(microbead)를 이용하여 MACS 자성 장비로 CD4 T 세포를 분리하였다. 분리된 CD4 T 세포는 CD3 항체 1 mg/mL로 자극하고 배양 플레이트에 접종한 후, CD28 항체 1 mg/mL로 처리하였다. 배양 배지는 10% FBS 및 1% 페니실린/스트렙토마이신(penicillin/streptomycin (PS))이 포함된 RPMI-1640 배지를 사용하여 37℃, 5% CO2 조건 하에 배양하였다.CD4 T cells were isolated from the spleen of B57BL/6 mice using a MACS magnetic instrument using CD4 microbeads. The isolated CD4 T cells were stimulated with 1 mg/mL of CD3 antibody, inoculated into culture plates, and treated with CD28 antibody at 1 mg/mL. The culture medium was 10% FBS and 1% penicillin / streptomycin (penicillin / streptomycin (PS)) using RPMI-1640 medium containing 37 ℃, 5% CO 2 It was cultured under conditions.
배양된 T 세포는 각각 적합한 분화 요인을 처리하여 Th1 세포, Th17 세포 및 조절 T 세포(regulatory T cells)로 분화하였다. 사이토카인 IL-12 10 ng/mL를 처리하여 Th1 세포로 분화하고, 사이토카인 IL-6 10 ng/mL, TGF-β 1 ng/mL, anti-IFN-γ 항체 5 mg/mL 및 anti-IL-4 항체 5 mg/mL를 처리하여 Th17 세포로 분화하고, 사이토카인 IL-2 10 ng/mL 및 TGF-β 10 ng/mL를 처리하여 조절 T 세포(regulatory T cells)로 분화하였다. 각각의 세포에 대한 적합한 분화 요인들과 함께 화합물 10 μM를 함께 처리하여 분화의 억제/촉진 여부를 확인하였고, 유사 대조군으로 면역 조절 세포의 분화 촉진 물질인 레티노산(Retionic acid, RA) 1 μM을 사용하였다.The cultured T cells were differentiated into Th1 cells, Th17 cells and regulatory T cells by treatment with appropriate differentiation factors, respectively. Treated with cytokine IL-12 10 ng/mL to differentiate into Th1 cells, cytokine IL-6 10 ng/mL, TGF-
4일 동안 배양한 후, 세포를 PMA/ionomycin 및 golgi stop으로 4시간 동안 자극하고, PBS로 2번 세척하였다. 세척 후 Fix/Perm buffer를 이용하여 세포 표면에 구멍을 내고, PE-anti-IFN-γ 항체를 이용하여 유세포 분석기 (flow cytometry)를 통해 세포 분화 정도를 확인하였다. 도 1에 나타난 바와 같이, 화합물은 Th1 세포 및 Th17 세포로 분화되는 것을 억제하는 것으로 나타났으며, 조절 T 세포(CD25+Foxp3+CD4+ T 세포)의 분화를 촉진하는 것으로 나타났다.After incubation for 4 days, the cells were stimulated with PMA/ionomycin and golgi stop for 4 hours, and washed twice with PBS. After washing, a hole was made on the cell surface using Fix/Perm buffer, and the degree of cell differentiation was checked through flow cytometry using PE-anti-IFN-γ antibody. As shown in FIG. 1 , the compound was shown to inhibit differentiation into Th1 cells and Th17 cells, and to promote differentiation of regulatory T cells (CD25+Foxp3+CD4+ T cells).
상기 결과는 화합물에는 염증 반응 및 면역 반응을 유도하는 헬퍼 T 세포의 분화를 억제하고 염증 반응 및 면역 반응을 억제하는 조절 T 세포의 분화를 촉진하는 활성이 있는 것으로 나타났으며, 상기 화합물이 염증 반응 및 면역 반응을 조절함으로써, 염증 질환 또는 면역 질환의 예방, 개선 또는 치료 효과가 있다는 것을 입증한다.The above results show that the compound has an activity of inhibiting the differentiation of helper T cells that induce inflammatory and immune responses, and promoting the differentiation of regulatory T cells that suppress the inflammatory and immune responses, and that the compound has an inflammatory response And by regulating the immune response, it is demonstrated that there is an effect of preventing, ameliorating or treating an inflammatory disease or an immune disease.
실시예 2. 본 발명에 따른 화합물의 세포 독성 평가Example 2. Evaluation of cytotoxicity of compounds according to the present invention
본 발명에 따른 본 발명에 따른 화합물의 세포 독성 여부를 확인하기 위해 CD4 T 세포에서 세포 독성을 평가하였다. CD4 T 세포에 다양한 농도(1 μM, 5 μM, 10 μM 및 20 μM)의 화합물을 처리하여 배양한 후, PI와 Annexin V로 염색하여 죽어가거나 사멸된 세포를 확인하였다. 도 2에 나타난 바와 같이, 화합물은 모든 농도에서 세포 독성이 나타나지 않았다.In order to determine whether the compound according to the present invention is cytotoxic, cytotoxicity was evaluated in CD4 T cells. CD4 T cells were treated with various concentrations (1 μM, 5 μM, 10 μM and 20 μM) of the compounds and cultured, and then stained with PI and Annexin V to identify dying or dead cells. As shown in FIG. 2 , the compound did not show cytotoxicity at any concentration.
실시예 3. 동물 모델에서 본 발명에 따른 화합물의 효과Example 3. Effect of a compound according to the invention in an animal model
본 발명에 따른 본 발명에 따른 화합물이 염증 질환 또는 면역 질환 동물모델에 미치는 영향을 확인하기 위해, 염증성 장질환 동물모델에 화합물을 투여하였다.In order to confirm the effect of the compound according to the present invention on an inflammatory disease or immune disease animal model, the compound was administered to an inflammatory bowel disease animal model.
8 내지 12 주령의 B57BL/6 마우스를 사용하였으며, 사육 조건은 사료와 물을 자유로이 공급하였고, 사육실 온도는 25±1℃, 상대습도는 50±10%로 유지하였으며, 자동조명 조절기를 이용하여 12 시간의 명암주기로 점등 관리하였다. 각각의 실험군은 5마리로 하여 난괴법(randomized block design)에 의하여 비투여 대조군, DSS(dioctyl sodium sulfosuccinate)만 단독 투여되는 질환 유도군 및 DSS 및 화합물을 함께 투여하는 군으로 나누어 실험하였다.B57BL/6 mice aged 8 to 12 weeks were used. Feed and water were freely supplied as breeding conditions, and the breeding room temperature was maintained at 25±1° C. and relative humidity at 50±10%. Lighting was managed with a light-dark cycle of time. In each experimental group, 5 animals were divided into a non-administered control group, a disease-inducing group in which only dioctyl sodium sulfosuccinate (DSS) was administered alone, and a group in which DSS and the compound were administered together by randomized block design.
DSS는 동물모델에 투여되어 염증성 장질환을 유발하였으며, DSS는 2.5% 농도로 정제수에 희석한 후, 6일 동안 일정한 주기로 경구 투여하였고, 화합물은 10mg/kg 용량으로 DSS와 함께 투여하였다. 화합물 투여에 따른 염증성 장질환의 개선 여부는 동물 모델의 체중 변화 및 혈변이 나타나는 정도로 확인하였다.DSS was administered to an animal model to induce inflammatory bowel disease, DSS was diluted in purified water to a concentration of 2.5%, and then orally administered at regular intervals for 6 days, and the compound was administered together with DSS at a dose of 10 mg/kg. Whether or not the inflammatory bowel disease was improved by the administration of the compound was confirmed to the extent that body weight changes and bloody stools appeared in the animal model.
동물 모델의 체중 변화는 실험 시작 시점부터 DSS 처리전 몸무게를 기준으로 10일 동안 일정시간에 Digital mass meter를 이용하여 동물 모델의 체중 변화를 관찰하였다. 혈변의 정도는 6일 간의 약물 투여 후, 4일이 지난 다음 동물 모델로부터 대장을 적출하여 육안으로 살펴보았다.The weight change of the animal model was observed using a digital mass meter for 10 days based on the body weight before DSS treatment from the start of the experiment using a digital mass meter. The degree of bloody stool was observed with the naked eye by removing the large intestine from the
도 3에 나타난 바와 같이, DSS를 투여한 동물모델은 3일째부터 몸무게가 현저하게 감소되는 반면, DDS 및 화합물을 함께 투여한 동물모델은 DSS만 투여된 동물모델에 비해 감소되는 정도가 상당히 억제되는 것을 확인하였고, DSS만 투여된 동물모델에 비해 DDS 및 화합물을 함께 투여한 동물모델에서 혈변의 정도가 유의적으로 감소하였다.As shown in Figure 3, the animal model administered with DSS significantly reduced body weight from the 3rd day, whereas the animal model administered with DDS and the compound showed a significant inhibition of the degree of reduction compared to the animal model administered with only DSS. It was confirmed that the degree of bloody stool was significantly reduced in the animal model administered with DDS and the compound compared to the animal model administered with only DSS.
또한, 상기 동물모델의 림프절에서 면역 세포를 분리하여 헬퍼 T 세포 및 조절 T 세포의 수를 계수하였다. 도 4에 나타난 바와 같이, DSS만 투여된 동물모델에 비해 DDS 및 화합물을 함께 투여한 동물모델에서 Th1 및 Th17 세포수가 유의적으로 감소하였으며, 조절 T 세포수는 현저히 증가한 것으로 나타났다.In addition, immune cells were isolated from the lymph nodes of the animal model, and the number of helper T cells and regulatory T cells was counted. As shown in FIG. 4 , compared to the animal model to which only DSS was administered, the number of Th1 and Th17 cells was significantly decreased in the animal model administered with DDS and the compound, and the number of regulatory T cells was significantly increased.
상기 결과는 염증성 장질환 동물모델에 화합물을 투여하면 체중 감소 및 혈변과 같은 증상을 개선하는 효과가 있으며, 염증 반응을 유도하는 헬퍼 T 세포의 수가 감소되고, 염증 반응을 억제하는 조절 T 세포 수가 증가하는 효과가 있다는 것을 입증한다.The above results show that when the compound is administered to an inflammatory bowel disease animal model, it has the effect of improving symptoms such as weight loss and bloody stool, the number of helper T cells inducing an inflammatory response is reduced, and the number of regulatory T cells that inhibit the inflammatory response is increased. prove that it works.
종합하면, 화합물에는 염증 반응 및 면역 반응을 억제하고, 염증 질환 또는 면역 질환의 증상을 개선하는 효과가 in vitro 및 in vivo 실험으로 확인되었으며, 이러한 결과는 화합물을 유효성분으로 포함하는 조성물은 염증 질환 또는 면역 질환의 예방, 개선 또는 치료용으로 사용될 수 있음을 입증한다.Taken together, the compound has the effect of suppressing inflammatory and immune responses, and improving the symptoms of inflammatory diseases or immune diseases through in vitro and in vivo experiments. Or it proves that it can be used for the prevention, improvement or treatment of immune diseases.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 즉, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다.As described above in detail a specific part of the present invention, for those of ordinary skill in the art, it is clear that this specific description is only a preferred embodiment, and the scope of the present invention is not limited thereby. Do. That is, the substantial scope of the present invention is defined by the appended claims and their equivalents.
Claims (13)
상기 염증 질환은 염증성 장질환, 피부염, 알레르기, 아토피, 결막염, 치주염, 비염, 중이염, 인후염, 편도염, 폐렴, 위궤양, 위염, 크론병, 대장염, 강직성 척추염, 건선관절염, 골관절염, 류마티스 관절염, 견관절주위염, 건염, 건초염, 건주위염, 근육염, 간염, 방광염, 신장염, 또는 쇼그렌 증후군(sjogren's syndrome)인 것을 특징으로 하는 약학적 조성물..As a pharmaceutical composition for the prevention or treatment of inflammatory diseases or immune diseases comprising geranylgeranyl pyrophosphate or a pharmaceutically acceptable salt thereof as an active ingredient,
The inflammatory disease is inflammatory bowel disease, dermatitis, allergy, atopic dermatitis, conjunctivitis, periodontitis, rhinitis, otitis media, pharyngitis, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, ankylosing spondylitis, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, periarthritis , Tendonitis, tendinitis, peritenitis, myositis, hepatitis, cystitis, nephritis, or Sjogren's syndrome (sjogren's syndrome), characterized in that the pharmaceutical composition..
상기 염증 질환은 염증성 장질환, 피부염, 알레르기, 아토피, 결막염, 치주염, 비염, 중이염, 인후염, 편도염, 폐렴, 위궤양, 위염, 크론병, 대장염, 강직성 척추염, 건선관절염, 골관절염, 류마티스 관절염, 견관절주위염, 건염, 건초염, 건주위염, 근육염, 간염, 방광염, 신장염, 또는 쇼그렌 증후군(sjogren's syndrome)인 것을 특징으로 하는 건강기능 식품 조성물.As a health functional food composition for the prevention or improvement of inflammatory diseases or immune diseases comprising geranylgeranyl pyrophosphate or a pharmaceutically acceptable salt thereof as an active ingredient,
The inflammatory disease is inflammatory bowel disease, dermatitis, allergy, atopic dermatitis, conjunctivitis, periodontitis, rhinitis, otitis media, pharyngitis, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, ankylosing spondylitis, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, periarthritis , Tendonitis, tendinitis, peritenitis, myositis, hepatitis, cystitis, nephritis, or a health functional food composition, characterized in that Sjogren's syndrome (sjogren's syndrome).
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| M. TIMILSHINA et al., CELL REPORTS, 27, pp.2948-2961, e1-e7, 2019 |
| SONJA M LACHER ET AL, CELL DEATH _ DISEASE, 2017, 8, E2824 |
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