KR20240031874A - Pharmaceutical composition for preventing or treating autoimmune disease, comprising glycogen phosphorylase (PYGL) inhibitor - Google Patents
Pharmaceutical composition for preventing or treating autoimmune disease, comprising glycogen phosphorylase (PYGL) inhibitor Download PDFInfo
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- KR20240031874A KR20240031874A KR1020230083836A KR20230083836A KR20240031874A KR 20240031874 A KR20240031874 A KR 20240031874A KR 1020230083836 A KR1020230083836 A KR 1020230083836A KR 20230083836 A KR20230083836 A KR 20230083836A KR 20240031874 A KR20240031874 A KR 20240031874A
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- disease
- pygl
- glycogen phosphorylase
- autoimmune diseases
- autoimmune
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Abstract
본 발명은 글리코겐 포스포릴라제(PYGL) 저해제를 유효성분으로 포함하는 자가면역 질환의 예방 또는 치료용 약학 조성물을 제공하고, 자가면역 질환의 예방 또는 치료용 물질을 스크리닝 하는 방법을 제공한다.
본 발명의 글리코겐 포스포릴라제(PYGL) 저해제를 유효성분으로 포함하는 자가면역 질환의 예방 또는 치료용 약학 조성물을 통해 궤양성 대장염 등의 자가면역 질환을 예방 또는 치료할 수 있다. 또한, 본 발명의 자가면역 질환의 예방 또는 치료용 물질의 스크리닝 방법을 통해 글리코겐 포스포릴라제(PYGL) 활성을 감소시키는 물질을 자가면역 질환의 예방 또는 치료용 물질의 후보물질로 결정할 수 있다.The present invention provides a pharmaceutical composition for the prevention or treatment of autoimmune diseases containing a glycogen phosphorylase (PYGL) inhibitor as an active ingredient, and a method for screening substances for the prevention or treatment of autoimmune diseases.
Autoimmune diseases such as ulcerative colitis can be prevented or treated through a pharmaceutical composition for preventing or treating autoimmune diseases containing the glycogen phosphorylase (PYGL) inhibitor of the present invention as an active ingredient. In addition, through the screening method for substances for the prevention or treatment of autoimmune diseases of the present invention, substances that reduce glycogen phosphorylase (PYGL) activity can be determined as candidates for substances for the prevention or treatment of autoimmune diseases.
Description
본 발명은 글리코겐 포스포릴라제(PYGL) 저해제를 유효성분으로 포함하는 자가면역 질환의 예방 또는 치료용 약학 조성물 및 자가면역 질환의 예방 또는 치료용 물질의 스크리닝 방법에 관한 것이다.The present invention relates to a pharmaceutical composition for the prevention or treatment of autoimmune diseases containing a glycogen phosphorylase (PYGL) inhibitor as an active ingredient and a screening method for substances for the prevention or treatment of autoimmune diseases.
면역은 생체 조직으로 침입하거나 주입되는 모든 외부 고분자물질에 대한 생체의 자기보호체계의 하나로 모든 정상 개체는 자기(self)를 구성하는 항원에 대해서는 해롭게 반응하지 않는 반면, 비자기(non-self) 항원에 대해서는 이를 인식하고 반응하여 제거할 수 있는 능력을 갖는다. 그러나 숙주의 면역 반응이 외래 항원을 자기항원과 구별하는데 실패하여 비정상적인 면역반응을 유도하면 체내의 면역세포가 자신의 세포성분을 공격하여 다양한 질병을 일으키는데, 이를 자가면역 질환이라고 한다.Immunity is one of the body's self-protection systems against all foreign polymers that invade or are injected into biological tissues. While all normal individuals do not react harmfully to antigens that constitute the self, non-self antigens It has the ability to recognize, react to, and eliminate it. However, when the host's immune response fails to distinguish foreign antigens from self-antigens and induces an abnormal immune response, the body's immune cells attack the body's own cellular components, causing various diseases, which are called autoimmune diseases.
자가면역 질환은 유전성, 스트레스, 호르몬, 중금속, 음식, 감염, 살충제 등 다양한 원인에 의해 발병하며, 전세계적으로 약 5 내지 8%에서 나타난다. 자가면역 질환의 예로는 염증성 장 질환, 자폐증, 천식, 제1형 당뇨병, 류마티스성 관절염, 류마티스성 다발성 근육통, 강직성 척추염, 건선성 관절염, 건선, 습진, 피부경화증, 백반, 다발성 경화증, IL-17 유발성 치매, 말초성 신경염, 포도막염, 안구건조증, 장기이식 거부, 암 등이 있다. 현재 자가면역 질환 치료제로서 항염증 및 면역 억제제 약물이 사용되고 있으나, 일부 환자들은 상기 약물들에 내성이 있어 치료가 어렵다.Autoimmune diseases are caused by various causes such as genetics, stress, hormones, heavy metals, food, infections, and pesticides, and occur in approximately 5 to 8% of cases worldwide. Examples of autoimmune diseases include inflammatory bowel disease, autism, asthma, type 1 diabetes, rheumatoid arthritis, polymyalgia rheumatica, ankylosing spondylitis, psoriatic arthritis, psoriasis, eczema, scleroderma, vitiligo, multiple sclerosis, and IL-17. These include induced dementia, peripheral neuritis, uveitis, dry eye syndrome, organ transplant rejection, and cancer. Currently, anti-inflammatory and immunosuppressive drugs are used as treatments for autoimmune diseases, but some patients are resistant to these drugs and thus difficult to treat.
상기 자가면역 질환 중, 염증성 장 질환(Inflammatory bowel disease)은 장에 만성적인 원인불명의 염증을 일으키는 질환이다. 상기 염증성 장 질환은 궤양성 대장염(ulcerative colitis, UC) 및 크론병(Crohn’s disease)을 포함하고, 정확한 병인은 아직 밝혀지지 않았으나, 유전학적 소인이 있는 사람에서 장관 내 세균에 대해 부적절한 면역반응에 의해 유발된다. 선천면역세포인 호중구와 대식세포는 물론 후천면역세포인 림프구 등 장면역계의 지속적이거나 부적절한 활성화는 결국 점막 파괴 및 궤양을 초래한다. 염증 상태의 장관의 점막에서 다양한 염증성 사이토카인들이 생성·분비되며 이 중 TNF-α(종양괴사인자-α)는 궤양성 대장염 환자의 대장 루멘과 대장 상피세포에서 높게 나타나며, 최근 연구에 의하면, TNF-α는 궤양성 대장염의 병인으로 중요한 역할을 한다고 알려졌다.Among the above autoimmune diseases, inflammatory bowel disease is a disease that causes chronic inflammation of unknown cause in the intestines. The inflammatory bowel disease includes ulcerative colitis (UC) and Crohn's disease, and although the exact etiology has not yet been identified, it is caused by an inappropriate immune response to intestinal bacteria in people with a genetic predisposition. It is triggered. Continuous or inappropriate activation of the intestinal immune system, including neutrophils and macrophages, which are innate immune cells, as well as lymphocytes, which are adaptive immune cells, ultimately results in mucosal destruction and ulceration. Various inflammatory cytokines are produced and secreted in the intestinal mucosa in an inflamed state, and among these, TNF-α (tumor necrosis factor-α) is highly expressed in the colonic lumen and colonic epithelial cells of patients with ulcerative colitis. According to a recent study, TNF-α (tumor necrosis factor-α) is highly expressed in the colonic lumen and colonic epithelial cells of patients with ulcerative colitis. -α is known to play an important role in the pathogenesis of ulcerative colitis.
항TNF-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. Janus kinase(JAK) 억제제인 토파시티닙(tofacitinib, Xeljanz®)이 궤양성 대장염에 치료 효능이 있으나, 크론병에는 효능이 없는 것으로 확인되고 있다. 즉, 아직까지 염증성 장 질환에 대해 신뢰할 만한 경구용 치료 요법이 없으므로, 이러한 질환에 대해 효과적이고 저비용의 경구용 치료제의 개발이 요구되고 있다.Infliximab, an anti-TNF-α antibody, is known to be effective not only in the treatment of boils but also in 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. Tofacitinib (Xeljanz®), a Janus kinase (JAK) inhibitor, has been found to be effective in treating ulcerative colitis, but not effective in Crohn's disease. In other words, since there is still no reliable oral treatment for inflammatory bowel disease, there is a need to develop an effective and low-cost oral treatment for these diseases.
상기 자가면역 질환 중, 류마티스 관절염(Rheumatoid arthritis)은 성인 인구의 약 1%를 차지할 정도로 흔한 질환이며 대부분의 환자에서 관절 파괴와 이로 인한 관절 변형이 나타나고 결국에는 불구를 초래하는 질환이다. 류마티스 관절염의 병태생리는 바이러스나 박테리아 감염에 따른 염증반응 후, 콜라겐(collagen)이나 프로테오글리칸(proteoglycan)과 같은 관절 내의 항원이 만성 염증에 의해 neopeptide를 만들고 이들에 특이성이 있는 자가반응성 T세포를 활성화시키는 것에 의한다고 보고되고 있으며, T림프구뿐만 아니라, B림프구, 활막세포의 상호관련성도 잘 알려져 있다. 류마티스 관절염에 관여하는 중요한 사이토카인(cytokine)은 TNF-α, IL-1, IL-6이며 이들은 내피세포에서 부착분자(adhesion molecule)의 표현을 증가시켜 관절 내로 백혈구의 유입이 증가하도록 하고, 활막세포와 연골세포에서 기질금속단백질분해효소(matrix metalloproteinase)의 분비를 촉진시켜 조직의 파괴를 유도한다. 류마티스 관절염의 치료를 위해 새로 개발된 약물 중에 가장 대표적인 것이 바로 항TNF-α 항체 제제이고 그 중에 가장 많이 사용되는 약물들이 현재까지 etanercept(Enbrel®), infliximab(Remicade®), adalimumab(Humira®)이다.Among the above autoimmune diseases, rheumatoid arthritis is a common disease that accounts for approximately 1% of the adult population, and most patients experience joint destruction and resulting joint deformation, ultimately leading to disability. The pathophysiology of rheumatoid arthritis is caused by an inflammatory response due to a viral or bacterial infection, in which antigens in the joint, such as collagen or proteoglycan, create neopeptides due to chronic inflammation and activate autoreactive T cells specific for these. It has been reported that this is due to the fact that not only T lymphocytes, but also B lymphocytes and synovial cells are well known. Important cytokines involved in rheumatoid arthritis are TNF-α, IL-1, and IL-6, which increase the expression of adhesion molecules in endothelial cells, increasing the influx of leukocytes into the joint and synovial membrane. It induces tissue destruction by promoting the secretion of matrix metalloproteinase from cells and cartilage cells. Among the newly developed drugs for the treatment of rheumatoid arthritis, the most representative ones are anti-TNF-α antibody preparations, and among them, the most commonly used drugs are etanercept (Enbrel®), infliximab (Remicade®), and adalimumab (Humira®). .
그러나, 이들 약제가 고가이고 투약의 불편함 등은 치료에 걸림돌이 되고 있다. 최근 경구투여가 가능한 류마티스 관절염 치료제로 개발된 토파시티닙의 경우, 류마티스 관절염 환자를 대상으로 한 일련의 임상시험에서 나타난 '중대한 (serious)' 감염 사례로서 게실염이 보고되었고, 특히 임상시험에서 위장관 천공 사례 중 하나인 게실천공이 보고되면서, 2015년 12월, FDA로부터 '주의', '이상반응' 섹션이 모두 업데이트 되었다. 현재까지 류마티스 관절염에 대해 가장 효과적인 치료 타겟으로 대두된 TNF-α 또는 TNF 수용체를 타겟으로 하는 약물로서 안전하고 효능이 뛰어난 경구용 치료제의 개발은 없는 상황이므로 이를 타겟으로 하는 효과적이고 저 비용의 경구용인 안전하고 효능이 뛰어난 류마티스 관절염 치료제의 개발이 요구되고 있다.However, these drugs are expensive and the inconvenience of administration is an obstacle to treatment. In the case of tofacitinib, which was recently developed as an orally administered rheumatoid arthritis treatment, diverticulitis was reported as a 'serious' infection case in a series of clinical trials targeting rheumatoid arthritis patients, and in particular, gastrointestinal perforation in clinical trials. As one of the cases, diverticular perforation, was reported, both the 'Cautions' and 'Adverse Reactions' sections were updated by the FDA in December 2015. To date, there has been no development of a safe and highly effective oral treatment targeting TNF-α or the TNF receptor, which has emerged as the most effective treatment target for rheumatoid arthritis. Therefore, an effective and low-cost oral treatment targeting this has not been developed. There is a need for the development of safe and highly effective treatments for rheumatoid arthritis.
본 발명의 해결 과제는 자가면역 질환의 예방 또는 치료용 물질을 스크리닝하는 방법을 제공하고, 이에 따라 선별된 물질을 유효성분으로 포함하는 자가면역 질환의 예방 또는 치료용 약학 조성물을 제공하는 것이다. The problem of the present invention is to provide a method for screening substances for the prevention or treatment of autoimmune diseases, and to provide a pharmaceutical composition for the prevention or treatment of autoimmune diseases containing the substances selected accordingly as active ingredients.
또한, 본 발명의 해결 과제는 상기 선별된 물질을, 이를 필요로 하는 대상(subject)에게 투여하는 단계를 포함하는 자가면역 질환의 예방 또는 치료 방법을 제공하는 것이다.In addition, the problem of the present invention is to provide a method for preventing or treating autoimmune diseases, including the step of administering the selected substance to a subject in need.
또한, 본 발명의 해결 과제는 자가면역 질환의 예방 또는 치료에 사용하기 위한 약제(medicament)를 제조하기 위한, 상기 선별된 물질의 용도(use)를 제공하는 것이다.In addition, the problem of the present invention is to provide a use of the selected substances for producing a medicament for use in the prevention or treatment of autoimmune diseases.
본 발명이 해결하고자 하는 과제는 이상에서 언급한 해결 과제로 제한되지 않으며, 언급되지 않은 또 다른 기술적 과제들은 아래의 기재로부터 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.The problem to be solved by the present invention is not limited to the problems mentioned above, and other technical problems not mentioned can be clearly understood by those skilled in the art from the description below. There will be.
상기 기술적 과제를 달성하기 위하여, 본 발명의 일 측면에 따라, 글리코겐 포스포릴라제(PYGL) 저해제를 유효성분으로 포함하는 자가면역 질환의 예방 또는 치료용 약학 조성물이 제공된다.In order to achieve the above technical problem, according to one aspect of the present invention, a pharmaceutical composition for preventing or treating autoimmune diseases containing a glycogen phosphorylase (PYGL) inhibitor as an active ingredient is provided.
본 발명의 다른 측면에 따라, 1) 글리코겐 포스포릴라제(PYGL)에 시험 물질을 처리하는 단계; 2) 글리코겐 포스포릴라제(PYGL)의 활성을 측정하는 단계; 및 3) 상기 글리코겐 포스포릴라제(PYGL)의 활성을 감소시키는 시험 물질을 자가면역 질환 치료제의 후보 물질로 결정하는 단계를 포함하는, 자가면역 질환의 예방 또는 치료용 물질의 스크리닝 방법이 제공된다.According to another aspect of the invention, 1) treating the test substance with glycogen phosphorylase (PYGL); 2) measuring the activity of glycogen phosphorylase (PYGL); and 3) determining a test substance that reduces the activity of glycogen phosphorylase (PYGL) as a candidate for the treatment of autoimmune diseases. A screening method for a substance for the prevention or treatment of autoimmune diseases is provided. .
본 발명의 또 다른 측면에 따라, 상기 글리코겐 포스포릴라제(PYGL) 저해제를, 이를 필요로 하는 대상에게 투여하는 단계를 포함하는 자가면역 질환의 예방 또는 치료 방법이 제공된다.According to another aspect of the present invention, a method for preventing or treating an autoimmune disease is provided, comprising administering the glycogen phosphorylase (PYGL) inhibitor to a subject in need thereof.
본 발명의 또 다른 측면에 따라, 자가면역 질환의 예방 또는 치료에 사용하기 위한 약제를 제조하기 위한, 상기 글리코겐 포스포릴라제(PYGL) 저해제의 용도가 제공된다.According to another aspect of the invention, there is provided the use of said glycogen phosphorylase (PYGL) inhibitor for the manufacture of a medicament for use in the prevention or treatment of autoimmune diseases.
본 발명의 글리코겐 포스포릴라제(PYGL) 저해제를 유효성분으로 포함하는 자가면역 질환의 예방 또는 치료용 약학 조성물을 통해 궤양성 대장염 및 류마티스성 관절염 등의 자가면역 질환을 예방 또는 치료할 수 있다.Autoimmune diseases such as ulcerative colitis and rheumatoid arthritis can be prevented or treated through a pharmaceutical composition for preventing or treating autoimmune diseases containing the glycogen phosphorylase (PYGL) inhibitor of the present invention as an active ingredient.
본 발명의 자가면역 질환의 예방 또는 치료용 물질의 스크리닝 방법을 통해 글리코겐 포스포릴라제(PYGL) 활성을 감소시키는 물질을 자가면역 질환의 예방 또는 치료용 물질의 후보물질로 결정할 수 있다.Through the screening method for substances for the prevention or treatment of autoimmune diseases of the present invention, substances that reduce glycogen phosphorylase (PYGL) activity can be determined as candidates for substances for the prevention or treatment of autoimmune diseases.
본 발명의 효과는 상기한 효과로 한정되는 것은 아니며, 본 발명의 설명 또는 청구범위에 기재된 발명의 구성으로부터 추론 가능한 모든 효과를 포함하는 것으로 이해되어야 한다.The effects of the present invention are not limited to the effects described above, and should be understood to include all effects that can be inferred from the configuration of the invention described in the description or claims of the present invention.
첨부된 도면은 해당 기술 분야의 통상의 기술자에게 본 발명의 내용을 보다 상세하게 설명하기 위한 것으로 본 발명의 기술적 사상이 이에 한정되는 것은 아니다.
도 1은 시험물질(INV-101, CP-91149 및 UC-205686)의 in vitro PYGL 저해능을 나타내는 그래프이다.
도 2a는 TNBS에 의해 유도된 질환 모델 랫트의 체중변화를 나타낸 그래프이다.
도 2b는 TNBS에 의해 유도된 후 8일차의 랫트의 체중을 나타낸 그래프이다.
도 3은 TNBS에 의해 유도된 질환 모델 랫트의 질병 진행 정도를 나타낸 그래프이다.
도 4는 TNBS에 의해 유도된 질환 모델 랫트의 대장의 형태학적 변화를 나타낸 사진이다.
도 5는 TNBS에 의해 유도된 질환 모델 랫트의 대장의 단위 길이당 무게를 나타낸 그래프이다.
도 6은 TNBS에 의해 유도된 질환 모델 랫트의 대장 조직의 H&E 염색 사진이다.
도 7은 TNBS에 의해 유도된 질환 모델 랫트의 대장 조직의 손상 정도 점수를 나타낸 그래프이다.
도 8은 TNBS에 의해 유도된 질환 모델 랫트의 대장 조직에서 염증 사이토카인 발현을 나타낸 것이다.
도 9a는 TNBS에 의해 유도된 질환 모델 랫트의 대장 조직의 염증 신호 활성화 정도를 나타낸 것이다(RIP1, RIP3, JAK1, JAK2, JAK3).
도 9b는 TNBS에 의해 유도된 질환 모델 랫트의 대장 조직의 염증 신호 활성화 정도를 나타낸 것이다(STAT1, STAT3, NF-κB).
도 10은 TNBS에 의해 유도된 질환 모델 랫트의 대장 조직의 MPO 변화를 나타낸 그래프이다.
도 11a는 TNBS에 의해 유도된 질환 모델 랫트의 혈중 TNFα 농도를 나타낸 그래프이다.
도 11b는 TNBS에 의해 유도된 질환 모델 랫트의 혈중 IL-6 농도를 나타낸 그래프이다.
도 11c는 TNBS에 의해 유도된 질환 모델 랫트의 혈중 IL-1β 농도를 나타낸 그래프이다.
도 11d는 TNBS에 의해 유도된 질환 모델 랫트의 혈중 CRP 농도를 나타낸 그래프이다.
도 12a는 TNBS에 의해 유도된 질환 모델 랫트의 혈중 글리코겐 포스포릴라제(PYGL) 농도를 나타낸 그래프이다.
도 12b는 TNBS에 의해 유도된 질환 모델 랫트의 혈중(serum) 글리코겐 포스포릴라제(PYGL) 활성을 나타낸 그래프이다.
도 13은 TNBS에 의해 유도된 질환 모델 랫트의 대장 조직의 글리코겐 포스포릴라제(PYGL) 활성을 나타낸 그래프이다.The attached drawings are intended to explain the present invention in more detail to those skilled in the art, and the technical idea of the present invention is not limited thereto.
Figure 1 is a graph showing the in vitro PYGL inhibition ability of test substances (INV-101, CP-91149, and UC-205686).
Figure 2a is a graph showing body weight changes in disease model rats induced by TNBS.
Figure 2b is a graph showing the body weight of rats on day 8 after induction by TNBS.
Figure 3 is a graph showing the degree of disease progression in disease model rats induced by TNBS.
Figure 4 is a photograph showing morphological changes in the large intestine of a disease model rat induced by TNBS.
Figure 5 is a graph showing the weight per unit length of the large intestine of a disease model rat induced by TNBS.
Figure 6 is a photograph of H&E staining of colon tissue of a disease model rat induced by TNBS.
Figure 7 is a graph showing the damage score of colonic tissue in a disease model rat induced by TNBS.
Figure 8 shows the expression of inflammatory cytokines in the colonic tissue of a disease model rat induced by TNBS.
Figure 9a shows the degree of inflammatory signal activation (RIP1, RIP3, JAK1, JAK2, JAK3) in colon tissue of a disease model rat induced by TNBS.
Figure 9b shows the degree of inflammatory signal activation (STAT1, STAT3, NF-κB) in colonic tissue of a disease model rat induced by TNBS.
Figure 10 is a graph showing changes in MPO in colon tissue of a disease model rat induced by TNBS.
Figure 11a is a graph showing the concentration of TNFα in the blood of a disease model rat induced by TNBS.
Figure 11b is a graph showing the concentration of IL-6 in the blood of a disease model rat induced by TNBS.
Figure 11c is a graph showing the concentration of IL-1β in the blood of TNBS-induced disease model rats.
Figure 11d is a graph showing the blood CRP concentration of a disease model rat induced by TNBS.
Figure 12a is a graph showing the concentration of glycogen phosphorylase (PYGL) in the blood of a disease model rat induced by TNBS.
Figure 12b is a graph showing the serum glycogen phosphorylase (PYGL) activity of a disease model rat induced by TNBS.
Figure 13 is a graph showing glycogen phosphorylase (PYGL) activity in colon tissue of a disease model rat induced by TNBS.
본 발명은, 글리코겐 포스포릴라제(PYGL) 저해제를 유효성분으로 포함하는 자가면역 질환의 예방 또는 치료용 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating autoimmune diseases containing a glycogen phosphorylase (PYGL) inhibitor as an active ingredient.
본 발명은 또한, 상기 글리코겐 포스포릴라제(PYGL) 저해제를, 이를 필요로 하는 대상에게 투여하는 단계를 포함하는 자가면역 질환의 예방 또는 치료 방법을 제공한다.The present invention also provides a method for preventing or treating autoimmune diseases, comprising administering the glycogen phosphorylase (PYGL) inhibitor to a subject in need thereof.
본 발명은 또한, 자가면역 질환의 예방 또는 치료에 사용하기 위한 약제를 제조하기 위한, 상기 글리코겐 포스포릴라제(PYGL) 저해제의 용도를 제공한다.The present invention also provides the use of the glycogen phosphorylase (PYGL) inhibitor for the manufacture of a medicament for use in the prevention or treatment of autoimmune diseases.
글리코겐 포스포릴라제(glycogen phosphorylase[PYGL], 글리코겐 가인산분해효소, 글리코겐 인산화효소)는 말단 알파-1-글리코시드 결합에서 글루코오스-1,4-포스페이트를 방출함으로써 동물에서 글리코겐의 분해를 촉매하는 효소이다. 이 효소는 활성 인산화 형태인 포스포릴라제 A(phosphorylase A)와 비활성 인산화 형태인 포스포릴라제 B(phosphorylase B)의 두 가지 형태로 존재하고, 두 가지 형태는 모두 동종이량체로 존재한다. PYGL 저해제의 글리코겐 분해 억제 효과를 이용하여 당뇨병 치료제 연구가 많이 진행되었다. 본 발명에서, PYGL 저해제는 면역반응과 관련된 세포내 신호전달 및 ROS 발생을 조절하여 면역세포 매개 염증반응을 조절함으로써 자가면역 질환 치료 효과를 가진다. 기존에 알려진 자가면역 질환 치료제 약물들은 사이토카인을 저해하는 메커니즘을 가지고 있어 예기치 못한 부작용이 발생할 수 있으나, PYGL 저해제는 면역세포 대사 조절을 통해 염증반응을 조절하여 자가면역 질환을 치료하는 것이므로 위와 같은 부작용이 없다는 장점이 있다.Glycogen phosphorylase (PYGL) catalyzes the breakdown of glycogen in animals by releasing glucose-1,4-phosphate from the terminal alpha-1-glycosidic bond. It is an enzyme. This enzyme exists in two forms, the active phosphorylated form, phosphorylase A, and the inactive phosphorylated form, phosphorylase B, and both forms exist as homodimers. Much research has been conducted on diabetes treatments using the glycogen breakdown inhibition effect of PYGL inhibitors. In the present invention, the PYGL inhibitor has the effect of treating autoimmune diseases by controlling immune cell-mediated inflammatory responses by regulating intracellular signaling and ROS generation related to immune responses. Existing drugs for the treatment of autoimmune diseases have mechanisms to inhibit cytokines, which may cause unexpected side effects. However, PYGL inhibitors treat autoimmune diseases by controlling the inflammatory response through regulation of immune cell metabolism, so the above side effects are not possible. There is an advantage to not having this.
본 발명에서는, 세포에서의 글리코겐 대사는 면역 세포의 염증 경로에 영향을 미치는 특정 신호를 조절함으로써 면역 세포 매개 염증 반응을 조절할 수 있음을 인지하고, 세포의 글리코겐 대사를 조절할 수 있는 PYGL 저해제를 자가면역 질환의 예방 또는 치료 용도로 사용하는 것을 제공한다.In the present invention, we recognize that glycogen metabolism in cells can regulate immune cell-mediated inflammatory responses by regulating specific signals that affect the inflammatory pathway of immune cells, and use a PYGL inhibitor that can regulate glycogen metabolism in cells to treat autoimmune diseases. It is provided for use in the prevention or treatment of diseases.
이에 따라, 현재 알려진 PYGL 저해제는 본 발명의 자가면역 질환의 예방 또는 치료 용도로 사용될 수 있다. 하기에 PYGL 저해제의 대표적인 예시를 들어 설명하지만, 이에 제한되는 것은 아니다.Accordingly, currently known PYGL inhibitors can be used for the prevention or treatment of autoimmune diseases of the present invention. Representative examples of PYGL inhibitors are described below, but are not limited thereto.
본 발명의 자가면역 질환의 예방 또는 치료 용도로 사용될 수 있는 PYGL 저해제의 일 예시는, WO 2008/057933(A2) 문헌의 하기 화학식 Ⅰ, 화학식 Ⅱ, 화학식 Ⅲ에 포함되는 물질이며, 구체적인 치환기 및 구체적 물질은 WO 2008/057933(A2)에 기재된 바와 같다.An example of a PYGL inhibitor that can be used for the prevention or treatment of autoimmune diseases of the present invention is a substance included in the following formulas I, formula II, and formula III of WO 2008/057933(A2), and has specific substituents and specific formulas. The material is as described in WO 2008/057933(A2).
, , , ,
본 발명의 자가면역 질환의 예방 또는 치료 용도로 사용될 수 있는 PYGL 저해제의 일 예시는, WO 2009/045831(A1) 문헌의 하기 화학식 Ⅰ(Formula Ⅰ), 화학식 ⅠA에 포함되는 물질과 실시예 1, 2의 물질이며, 구체적인 치환기 및 구체적 물질은 WO 2009/045831(A1)에 기재된 바와 같다.Examples of PYGL inhibitors that can be used for the prevention or treatment of autoimmune diseases of the present invention include substances included in Formula I and Formula IA and Example 1 of WO 2009/045831(A1). 2, and the specific substituents and specific materials are as described in WO 2009/045831(A1).
, ,
본 발명의 자가면역 질환의 예방 또는 치료 용도로 사용될 수 있는 PYGL 저해제의 일 예시는, WO 2019/246494(A1) 문헌의 하기 화학식 Ⅰ(Formula Ⅰ)과 실시예 1 내지 3에서 사용된 물질이며, 구체적인 치환기 및 구체적 물질은 WO 2019/246494 (A1)에 기재된 바와 같다.An example of a PYGL inhibitor that can be used for the prevention or treatment of autoimmune diseases of the present invention is the following Formula I and the substances used in Examples 1 to 3 of WO 2019/246494(A1), Specific substituents and specific materials are as described in WO 2019/246494 (A1).
본 발명의 자가면역 질환의 예방 또는 치료 용도로 사용될 수 있는 PYGL 저해제의 일 예시는, WO 2022/160138(A1) 문헌의 하기 화학식 Ⅰ과 실시예의 물질이며, 구체적인 치환기 및 구체적 물질은 WO 2022/160138(A1)에 기재된 바와 같다.An example of a PYGL inhibitor that can be used for the prevention or treatment of autoimmune diseases of the present invention is the substance of the following formula I and examples in WO 2022/160138(A1), and specific substituents and specific substances are described in WO 2022/160138 As described in (A1).
보다 구체적으로, 상기 글리코겐 포스포릴라제(PYGL) 저해제는 하기 화학식 1 내지 8 로 표시되는 화합물로 이루어지는 군으로부터 선택되는 1종 이상일 수 있으나, 이에 제한되는 것은 아니다.More specifically, the glycogen phosphorylase (PYGL) inhibitor may be one or more selected from the group consisting of compounds represented by the following formulas 1 to 8, but is not limited thereto.
하기 화학식 1 로 표시되는 화합물은 N-(5-하이드록시-3,4,6-트라이메틸피리딘-2-일)-5-메틸-1H-인돌-2-카복사마이드 (INV-101)이다.The compound represented by the following formula 1 is N-(5-hydroxy-3,4,6-trimethylpyridin-2-yl)-5-methyl-1H-indole-2-carboxamide (INV-101) .
하기 화학식 2로 표시되는 화합물은 CP-91149이다.The compound represented by the following formula (2) is CP-91149.
하기 화학식 3으로 표시되는 화합물은 UC-205686이다.The compound represented by the following formula (3) is UC-205686.
하기 화학식 4로 표시되는 화합물은 PSN-357이다.The compound represented by the following formula (4) is PSN-357.
하기 화학식 5로 표시되는 화합물은 GSK-1362885이다.The compound represented by the following formula (5) is GSK-1362885.
하기 화학식 6으로 표시되는 화합물은 CP-368296(Ingliforib)이다.The compound represented by the following formula (6) is CP-368296 (Ingliforib).
하기 화학식 7로 표시되는 화합물은 Z13865200141이다.The compound represented by the following formula (7) is Z13865200141.
하기 화학식 8로 표시되는 화합물은 AVE-5688이다.The compound represented by Formula 8 below is AVE-5688.
<화학식 1><Formula 1>
<화학식 2><Formula 2>
<화학식 3><Formula 3>
<화학식 4><Formula 4>
<화학식 5><Formula 5>
<화학식 6><Formula 6>
<화학식 7><Formula 7>
<화학식 8><Formula 8>
일 구현예에서, 상기 자가면역 질환은 염증성 장 질환, 천식, 제1형 당뇨병, 류마티스성 관절염, 류마티스성 다발성 근육통, 강직성 척추염, 건선성 관절염, 건선, 습진, 피부경화증, 백반, 다발성 경화증, 인터루킨-17(IL-17) 유발성 치매, 말초성 신경염, 포도막염, 다발성 근육염 및 피부 근육염, 자가면역 혈구감소증, 자가면역 심근염, 아토피피부염, 일차성간경변, 안구건조증, 섬유근육통, 굿파이처 증후군, 자가면역 뇌수막염, 쇼그렌 증후군, 전신 홍반성 루프스, 애디슨병, 원형 탈모증, 자가면역성 간염, 자가면역성 이하선염, 이영양성 수포성 표피박리증, 부고환염, 사구체 신염, 그레이브스병, 셀리악병, 길랑바레 증후군, 하시모토병, 용혈성 빈혈, 중증 근무력증, 근위축성측색경화증, 심상천포창, 류마티스열, 유육종증, 피부 경화증, 척추관절증, 갑상선염, 혈관염, 백반증, 점액수종, 악성빈혈, 항인지질증후군, 고형장기 이식 후기 및 만성 거부증, 및 이식편대숙주질환으로 이루어진 군으로부터 선택되는 1종 이상일 수 있다.In one embodiment, the autoimmune disease is inflammatory bowel disease, asthma, type 1 diabetes, rheumatoid arthritis, polymyalgia rheumatica, ankylosing spondylitis, psoriatic arthritis, psoriasis, eczema, scleroderma, vitiligo, multiple sclerosis, interleukin -17 (IL-17) induced dementia, peripheral neuritis, uveitis, polymyositis and dermatomyositis, autoimmune cytopenia, autoimmune myocarditis, atopic dermatitis, primary cirrhosis, dry eye, fibromyalgia, Goodficher syndrome, autoimmune Immune meningitis, Sjogren's syndrome, systemic lupus erythematosus, Addison's disease, alopecia areata, autoimmune hepatitis, autoimmune parotitis, dystrophic epidermolysis bullosa, epididymitis, glomerulonephritis, Graves' disease, celiac disease, Guillain-Barre syndrome, Hashimoto's disease, Hemolytic anemia, myasthenia gravis, amyotrophic lateral sclerosis, pemphigus vulgaris, rheumatic fever, sarcoidosis, scleroderma, spondyloarthrosis, thyroiditis, vasculitis, vitiligo, myxedema, pernicious anemia, antiphospholipid syndrome, late solid organ transplantation and chronic rejection, and It may be one or more types selected from the group consisting of graft-versus-host disease.
일 구현예에서, 상기 염증성 장 질환은 장염, 대장염, 궤양성 대장염, 크론병, 크론친화성 세포종, 과민성 대장 증후군, 출혈성 직장 궤양, 회장낭 염(pouchitis), 소화성 궤양, 장관형 베체트병, 및 위염으로 이루어진 군으로부터 선택되는 1종 이상일 수 있다.In one embodiment, the inflammatory bowel disease includes enteritis, colitis, ulcerative colitis, Crohn's disease, Crohn's sarcoma, irritable bowel syndrome, bleeding rectal ulcer, ileal pouchitis, peptic ulcer, enteric Behcet's disease, and gastritis. It may be one or more types selected from the group consisting of.
일 구현예에서, 상기 염증성 장 질환은 궤양성 대장염일 수 있다. 궤양성 대장염은 대장의 점막 또는 점막하층에 염증 또는 궤양이 생기는 질환이며, 소장 및 대장 전체에 산발적으로 발생하는 염증성 장 질환인 크론병과는 다르게 직장에서 시작되어 대장 안쪽으로 연결된 병변을 특징으로 한다. 궤양성 대장염 환자의 대부분은 하루 수회의 혈액과 점액이 섞인 묽은 변 또는 설사를 하며, 심한 경우 복통, 탈수, 발열, 구토, 체중 감소 등의 증상을 호소한다. 대부분의 궤양성 대장염은 만성 재발성 경과를 보이며, 재발할수록 상태가 악화된다.In one embodiment, the inflammatory bowel disease may be ulcerative colitis. Ulcerative colitis is a disease in which inflammation or ulcers occur in the mucosa or submucosa of the large intestine. Unlike Crohn's disease, which is an inflammatory bowel disease that occurs sporadically throughout the small and large intestine, it is characterized by lesions that start in the rectum and connect to the inside of the large intestine. Most patients with ulcerative colitis have loose stools or diarrhea mixed with blood and mucus several times a day, and in severe cases, they complain of symptoms such as abdominal pain, dehydration, fever, vomiting, and weight loss. Most ulcerative colitis has a chronic recurrent course, and the condition worsens as it relapses.
또한, 본 발명은 1) 글리코겐 포스포릴라제(PYGL)에 시험 물질을 처리하는 단계; 2) 글리코겐 포스포릴라제(PYGL)의 활성을 측정하는 단계; 및 3) 상기 글리코겐 포스포릴라제(PYGL)의 활성을 감소시키는 시험 물질을 자가면역 질환 치료제의 후보 물질로 결정하는 단계를 포함하는, 자가면역 질환의 예방 또는 치료용 물질의 스크리닝 방법을 제공한다. In addition, the present invention includes the steps of 1) treating the test substance with glycogen phosphorylase (PYGL); 2) measuring the activity of glycogen phosphorylase (PYGL); and 3) determining a test substance that reduces the activity of glycogen phosphorylase (PYGL) as a candidate for the treatment of autoimmune diseases. It provides a screening method for substances for the prevention or treatment of autoimmune diseases. .
일 구현예에서, 상기 글리코겐 포스포릴라제(PYGL)의 활성의 측정은 글루코오스-1-포스페이트(G-1-P) 검출을 이용하여 측정하는 것일 수 있다. In one embodiment, the activity of glycogen phosphorylase (PYGL) may be measured using glucose-1-phosphate (G-1-P) detection.
상기 글루코오스-1-포스페이트(G-1-P)는 글리코겐이 글리코겐 포스포릴라제에 의해 분해되어 생성되는 물질이다. 글리코겐 포스포릴라제의 활성은 글루코오스-1-포스페이트의 검출 신호의 세기에 비례한다.The glucose-1-phosphate (G-1-P) is a substance produced by decomposition of glycogen by glycogen phosphorylase. The activity of glycogen phosphorylase is proportional to the intensity of the detection signal of glucose-1-phosphate.
일 구현예에서, 상기 자가면역 질환은 염증성 장 질환, 천식, 제1형 당뇨병, 류마티스성 관절염, 류마티스성 다발성 근육통, 강직성 척추염, 건선성 관절염, 건선, 습진, 피부경화증, 백반, 다발성 경화증, 인터루킨-17(IL-17) 유발성 치매, 말초성 신경염, 포도막염, 다발성 근육염 및 피부 근육염, 자가면역 혈구감소증, 자가면역 심근염, 아토피피부염, 일차성간경변, 안구건조증, 섬유근육통, 굿파이처 증후군, 자가면역 뇌수막염, 쇼그렌 증후군, 전신 홍반성 루프스, 애디슨병, 원형 탈모증, 자가면역성 간염, 자가면역성 이하선염, 이영양성 수포성 표피박리증, 부고환염, 사구체 신염, 그레이브스병, 셀리악병, 길랑바레 증후군, 하시모토병, 용혈성 빈혈, 중증 근무력증, 근위축성측색경화증, 심상천포창, 류마티스열, 유육종증, 피부 경화증, 척추관절증, 갑상선염, 혈관염, 백반증, 점액수종, 악성빈혈, 항인지질증후군, 고형장기 이식 후기 및 만성 거부증, 및 이식편대숙주질환으로 이루어진 군으로부터 선택되는 1종 이상일 수 있다.In one embodiment, the autoimmune disease is inflammatory bowel disease, asthma, type 1 diabetes, rheumatoid arthritis, polymyalgia rheumatica, ankylosing spondylitis, psoriatic arthritis, psoriasis, eczema, scleroderma, vitiligo, multiple sclerosis, interleukin -17 (IL-17) induced dementia, peripheral neuritis, uveitis, polymyositis and dermatomyositis, autoimmune cytopenia, autoimmune myocarditis, atopic dermatitis, primary cirrhosis, dry eye, fibromyalgia, Goodficher syndrome, autoimmune Immune meningitis, Sjogren's syndrome, systemic lupus erythematosus, Addison's disease, alopecia areata, autoimmune hepatitis, autoimmune parotitis, dystrophic epidermolysis bullosa, epididymitis, glomerulonephritis, Graves' disease, celiac disease, Guillain-Barre syndrome, Hashimoto's disease, Hemolytic anemia, myasthenia gravis, amyotrophic lateral sclerosis, pemphigus vulgaris, rheumatic fever, sarcoidosis, scleroderma, spondyloarthrosis, thyroiditis, vasculitis, vitiligo, myxedema, pernicious anemia, antiphospholipid syndrome, late solid organ transplantation and chronic rejection, and It may be one or more types selected from the group consisting of graft-versus-host disease.
일 구현예에서, 상기 염증성 장 질환은 장염, 대장염, 궤양성 대장염, 크론병, 크론친화성 세포종, 과민성 대장 증후군, 출혈성 직장 궤양, 회장낭 염(pouchitis), 소화성 궤양, 장관형 베체트병, 및 위염으로 이루어진 군으로부터 선택되는 1종 이상일 수 있다.In one embodiment, the inflammatory bowel disease includes enteritis, colitis, ulcerative colitis, Crohn's disease, Crohn's sarcoma, irritable bowel syndrome, bleeding rectal ulcer, ileal pouchitis, peptic ulcer, enteric Behcet's disease, and gastritis. It may be one or more types selected from the group consisting of.
일 구현예에서, 상기 염증성 장 질환은 궤양성 대장염일 수 있다.In one embodiment, the inflammatory bowel disease may be ulcerative colitis.
본 발명에 따른 상기 약학 조성물은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등 이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용된다. 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다.The pharmaceutical composition according to the present invention may be administered in various oral and parenteral dosage forms during clinical administration. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations contain one or more compounds and at least one excipient, such as starch, calcium carbonate, sucrose or lactose ( It is prepared by mixing lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate.
본 발명에 따른 상기 약학 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다. 이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 약학 조성물을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 포함할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.The pharmaceutical composition according to the present invention can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. At this time, in order to formulate a formulation for parenteral administration, the pharmaceutical composition is mixed with water along with a stabilizer or buffer to prepare a solution or suspension, which can be prepared in an ampoule or vial unit dosage form. The composition may be sterilized and/or contain preservatives, stabilizers, wetting agents or emulsification accelerators, auxiliaries such as salts and/or buffers for osmotic pressure adjustment, and other therapeutically useful substances, and may be mixed, granulated, etc. using conventional methods. It can be formulated according to the coating or coating method.
본 발명에 따른 상기 약학 조성물의 경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭시르제, 트로키제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌 글리콜)를 포함할 수 있다. 정제는 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘 등과 같은 결합제를 포함할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염 등과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제 및 감미제를 포함할 수 있다. Formulations for oral administration of the pharmaceutical composition according to the present invention include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc., and these formulations are effective In addition to the ingredients, diluents (e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (e.g. silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol) may include. The tablet may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and optionally a binder such as starch, agar, alginic acid or its sodium salt, etc. The releasing or boiling mixture may contain absorbents, colorants, flavoring and sweetening agents.
본 발명의 상기 부형제, 결합제, 붕해제, 활택제, 착색제, 향미제 등에 대한 용어 정의는 당업계에 공지된 문헌에 기재된 것으로 그 기능 등이 동일내지 유사한 것들을 포함한다.Definitions of the excipients, binders, disintegrants, lubricants, colorants, flavoring agents, etc. of the present invention are those described in literature known in the art and include those with the same or similar functions.
본 발명의 약학 조성물에 포함되는 유효성분의 투여량은 환자의 상태 및 체중, 질병의 정도, 유효성분 형태, 투여 경로 및 기간에 따라 다르며, 환자에 따라 적절하게 조절될 수 있다. 예를 들면, 상기 유효성분은 1일 0.0001 내지 1000 mg/kg으로, 바람직하게는 0.01 내지 1000 mg/kg의 용량으로 투여할 수 있으며, 상기 투여는 하루에 한번 또는 수회 나누어 투여할 수도 있다. 또한, 본 발명의 약학 조성물은 조성물 총 중량에 대하여 상기 유효성분을 0.001 내지 90 % 중량백분율로 포함할 수 있다.The dosage of the active ingredient included in the pharmaceutical composition of the present invention varies depending on the patient's condition and weight, degree of disease, form of the active ingredient, route and period of administration, and can be appropriately adjusted depending on the patient. For example, the active ingredient can be administered at a dose of 0.0001 to 1000 mg/kg per day, preferably 0.01 to 1000 mg/kg, and the administration may be administered once a day or in divided doses. Additionally, the pharmaceutical composition of the present invention may contain the active ingredient at a weight percentage of 0.001 to 90% based on the total weight of the composition.
이하, 본 발명을 실시예 및 실험예를 통하여 더욱 상세히 설명한다. 그러나, 하기 실시예 및 실험예는 본 발명을 예시하기 위한 것으로, 본 발명의 범위가 이에 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples and experimental examples. However, the following examples and experimental examples are intended to illustrate the present invention, and the scope of the present invention is not limited thereto.
실시예 1. PYGL 저해제Example 1. PYGL inhibitors
화합물 N-(5-하이드록시-3,4,6-트라이메틸피리딘-2-일)-5-메틸-1H-인돌-2-카복사마이드 [N-(5-hydroxy-3,4,6-trimethylpyridin-2-yl)-5-methyl-1H-indole-2-carboxamide, INV-101](하기 화학식 1)를 사용하여 PYGL 저해제가 염증을 억제하여 자가면역 질환에 대한 치료 효과를 나타내는 것을 확인하였다. 자가면역 질환의 염증 관련 질환으로서 염증성 장 질환을 선택하였고, 염증성 장 질환의 동물 모델을 확립하여 하기와 같이 실험을 수행하였다.Compound N-(5-hydroxy-3,4,6-trimethylpyridin-2-yl)-5-methyl-1H-indole-2-carboxamide [N-(5-hydroxy-3,4,6 -trimethylpyridin-2-yl)-5-methyl-1H-indole-2-carboxamide, INV-101] (Formula 1 below) was used to confirm that the PYGL inhibitor suppresses inflammation and exhibits a therapeutic effect on autoimmune diseases. did. Inflammatory bowel disease was selected as an inflammation-related autoimmune disease, an animal model of inflammatory bowel disease was established, and experiments were performed as follows.
<화학식 1><Formula 1>
1H-NMR ((CD3)2SO) δ 11.54 (d, J= 1.1 Hz, 1H), 10.22 (s, 1H), 8.63 (s, 1H), 7.41 (s, 1H), 7.30 (dd, J = 12.6, 4.9 Hz, 2H), 7.03 (dd, J = 8.4, 1.4 Hz, 1H), 2.36 (d, J = 8.1 Hz, 6H), 2.17 (s, 3H), 2.04 (s, 3H). 1 H-NMR ((CD 3 ) 2 SO) δ 11.54 (d, J= 1.1 Hz, 1H), 10.22 (s, 1H), 8.63 (s, 1H), 7.41 (s, 1H), 7.30 (dd, J = 12.6, 4.9 Hz, 2H), 7.03 (dd, J = 8.4, 1.4 Hz, 1H), 2.36 (d, J = 8.1 Hz, 6H), 2.17 (s, 3H), 2.04 (s, 3H).
실험예 1. 화합물 INV-101의 PYGL 저해능 확인 시험Experimental Example 1. Test to confirm the PYGL inhibition ability of compound INV-101
글리코겐 포스포릴라제(GPase)는 가역 반응인 (글루코스)n + Pi에서 (글루코스)n-1 + G-1-P로의 반응을 촉매한다. 반응은 글리코겐과 Pi가 순방향 반응으로 반응할 수 있는 조건이 되면 시작된다. 포스포릴라제 키나아제는 비활성 글리코겐 포스포릴라제 B를 완전 활성 글리코겐 포스포릴라제 A로 전환하는 것을 촉매한다. 그러나 전반적인 조절은 포스파타제(phosphatase)의 작용에서 AMP에 의한 피드백 제어에 이르기까지 다양한 요인의 상호 작용에 따라 달라진다. GPase는 간에서 혈당 수치 조절을 담당하는 주요 조절 효소이다. GPase 억제제는 제2형 당뇨병 치료에 유용할 수 있다.Glycogen phosphorylase (GPase) catalyzes the reversible reaction (glucose)n + Pi to (glucose)n-1 + G-1-P. The reaction begins when conditions allow glycogen and Pi to react in a forward reaction. Phosphorylase kinase catalyzes the conversion of inactive glycogen phosphorylase B to fully active glycogen phosphorylase A. However, overall regulation depends on the interaction of a variety of factors, ranging from the action of phosphatases to feedback control by AMPs. GPase is the main regulatory enzyme responsible for regulating blood sugar levels in the liver. GPase inhibitors may be useful in treating type 2 diabetes.
본 연구는 토끼 근육 글리코겐 포스포릴라아제(RMGPa)에 대한 INV-101(BJ-80F)의 억제 활성을 평가하여 RMGPa를 억제함으로써 면역 조절제로 개발될 수 있는 가능성을 알아보기 위해 수행되었다.This study was conducted to evaluate the inhibitory activity of INV-101 (BJ-80F) against rabbit muscle glycogen phosphorylase (RMGPa) to determine its potential to be developed as an immunomodulator by inhibiting RMGPa.
글리코겐 포스포릴라제 비색 분석 키트(Glycogen Phosphorylase Colorimetric Assay Kit)를 이용하고, 토끼 근육 글리코겐 포스포릴라제(RMGPa)를 사용하여, 화합물 INV-101의 PYGL 저해능을 확인하였다. 시험 물질 또는 비이클(vehicle, 1.0% DMSO 내)을 37 ℃에서 15분 동안 5μg/ml의 효소와 함께 변형된(modified) 이미다졸 완충액(pH 6.8)에서 사전 인큐베이션시켰다. 양성 대조군으로 UC-205686(0.03 μM) 및 CP-91149(3 μM)을 사용하였다. 반응은 다른 30분 인큐베이션 기간 동안 4mg/ml 글리코겐의 첨가로 개시되었다. 생성된 NADPH의 양은 340 nm에서 분광광도계로 분석하였다. 물질들은 정확한 IC50 분석을 위하여 최소 10개의 저해 농도(100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0 μM)에서 측정하였다. RMGPa의 활성은 글루코오스-1-포스페이트(glucose-1-phosphate)를 검출하여 측정하였다.The PYGL inhibition ability of compound INV-101 was confirmed using the Glycogen Phosphorylase Colorimetric Assay Kit and rabbit muscle glycogen phosphorylase (RMGPa). Test substances or vehicle (in 1.0% DMSO) were pre-incubated in modified imidazole buffer (pH 6.8) with 5 μg/ml enzyme for 15 minutes at 37°C. UC-205686 (0.03 μM) and CP-91149 (3 μM) were used as positive controls. The reaction was initiated with the addition of 4 mg/ml glycogen for another 30 min incubation period. The amount of NADPH produced was analyzed spectrophotometrically at 340 nm. Substances were measured at at least 10 inhibitory concentrations (100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0 μM) for accurate IC 50 analysis. The activity of RMGPa was measured by detecting glucose-1-phosphate.
상기 물질들의 RMGPa 저해능 결과는 도 1 및 하기 표 1과 같다. PYGL 저해제로 알려져 있는 CP-91149 및 UC-205686의 IC50는 각각 2.53 μM 및 0.016 μM이고, INV-101의 IC50는 0.085 μM 로 측정되었다. 상기 실험예 1 의 결과로부터, 본 발명의 화합물 INV-101은 강력한 PYGL 저해제임을 알 수 있다.The results of the RMGPa inhibition ability of the above substances are shown in Figure 1 and Table 1 below. The IC 50 of CP-91149 and UC-205686, known PYGL inhibitors, were 2.53 μM and 0.016 μM, respectively, and the IC 50 of INV-101 was measured at 0.085 μM. From the results of Experimental Example 1, it can be seen that the compound INV-101 of the present invention is a strong PYGL inhibitor.
(BJ-80F)INV-101
(BJ-80F)
실험예 2. TNBS로 유도한 염증성 장 질환 랫트 모델에서 PYGL 저해제인 화합물 INV-101의 경구 투여 Experimental Example 2. Oral administration of compound INV-101, a PYGL inhibitor, in a TNBS-induced inflammatory bowel disease rat model in vivoin vivo 효능 시험 efficacy test
염증성 장 질환의 동물모델은 여러 유형이 있으나 화학물질로 병변을 야기하는 모델이 자주 이용되고 있다. 마우스 또는 랫트에서 트리니트로벤젠 설폰산(TNBS)을 직장내에 주입하여 유도된 대장염은 염증성 장 질환의 한 형태인 크론병에 대한 기본 병리학적 및 면역학적 메커니즘을 연구할 수 있는 동물 모델 중 하나이다. TNBS로 유도한 염증성 장 질환 동물모델에서 필고티닙(Filgotinib)(30 mg/kg), UC-205686(10 mg/kg) 경구투여 그룹을 양성대조군으로 하여 INV-101의 경구투여 효능을 비교하였다.There are several types of animal models for inflammatory bowel disease, but models that cause lesions with chemicals are frequently used. Colitis induced by intrarectal injection of trinitrobenzene sulfonic acid (TNBS) in mice or rats is one of the animal models in which the basic pathological and immunological mechanisms of Crohn's disease, a form of inflammatory bowel disease, can be studied. In an inflammatory bowel disease animal model induced by TNBS, the efficacy of oral administration of INV-101 was compared using the oral administration group of Filgotinib (30 mg/kg) and UC-205686 (10 mg/kg) as a positive control group. .
1. 시험 방법1. Test method
(1) 실험동물 및 그룹화(1) Experimental animals and grouping
동물은 7-8주령된 랫트(Sprague Dawley Rat)를 오리엔트바이오(Korea)로부터 구입하여 7일간 일반 고형사료로 안정화시킨 후 실험에 이용하였다. 실험 기간 중 사료와 물을 자유로이 공급하였고, 사육실의 온도는 25±1 ℃, 상대습도는 50±10%로 유지시켰다. 점등 관리는 자동조명조절기에 의해 12시간 명암주기(light-dark cycle)로 조절하였다. 실험군은 각 군당 8마리로 하여 평균 체중이 250±20 g이 되도록 무작위 블록 설계(randomized block design)에 의하여 7군(정상군, TNBS-Vehicle 투여군, TNBS+Filgotinib 30 mg/kg 투여군, TNBS+UC-205686 10 mg/kg 투여군, TNBS+INV-101 1 mg/kg투여군, TNBS+INV-101 3 mg/kg투여군, TNBS+INV-101 10 mg/kg투여군)으로 나누어 실험하였다.The animals were 7-8 week old rats (Sprague Dawley Rats) purchased from Orient Bio (Korea) and stabilized with regular solid feed for 7 days before being used in the experiment. Feed and water were supplied ad libitum during the experiment, and the temperature in the breeding room was maintained at 25±1°C and relative humidity at 50±10%. Lighting management was controlled with a 12-hour light-dark cycle using an automatic lighting controller. The experimental group was divided into 7 groups (normal group, TNBS-Vehicle administered group, TNBS+Filgotinib 30 mg/kg administered group, TNBS+UC) by randomized block design with 8 animals in each group, with an average weight of 250±20 g. -205686 10 mg/kg administration group, TNBS+INV-101 1 mg/kg administration group, TNBS+INV-101 3 mg/kg administration group, TNBS+INV-101 10 mg/kg administration group).
(2) TNBS 직장 투여 장염 유발(2) Rectal administration of TNBS causes enteritis
24시간 절식한 랫트를 디에틸 에테르로 마취한 후, 폴리에틸렌 카테터를 연결한 1 mL 주사기를 이용하여 결장의 내강에 50 v/v% 에탄올로 희석한 5% TNBS를 0.8 mL을 천천히 주입한 후, 항문으로 5% TNBS가 새어 나오는 것을 방지하기 위하여 랫트를 거꾸로 세운 상태에서 60초 동안 정치시켰다. 대조군은 비이클(vehicle) [50v/v% ethanol]만을 다른 군과 마찬가지 방법으로 주입하였다.After anesthetizing a rat that had fasted for 24 hours with diethyl ether, 0.8 mL of 5% TNBS diluted with 50 v/v% ethanol was slowly injected into the lumen of the colon using a 1 mL syringe connected to a polyethylene catheter. To prevent 5% TNBS from leaking through the anus, the rat was left upside down for 60 seconds. The control group was injected with only vehicle [50v/v% ethanol] in the same manner as the other groups.
(3) 약물 투여(3) Drug administration
TNBS를 투여한 당일 약물 투여는 TNBS 투여 2시간 후 약물의 최초 경구 투여를 실시하고 다음 날부터 6일 동안 매일 일정한 시간에 경구 투여하였다.The first oral administration of the drug on the day of TNBS administration was conducted 2 hours after TNBS administration, and the drug was administered orally at a constant time every day for 6 days from the next day.
(4) 체중 관찰(4) Weight observation
디지털 체중계를 이용하여 절식 단계부터 TNBS 투여 및 약물 투여과정 동안 각 랫트의 체중 변화를 관찰하였다.Using a digital scale, we observed the change in body weight of each rat from the fasting phase to the TNBS administration and drug administration process.
(5) 심장채혈 및 혈액 분석(5) Heart blood collection and blood analysis
최후 약물 투여 전 24시간 절식시킨 후 최후 약물 투여 1시간 내에 랫트를 마취시킨 후 심장채혈을 실시하였다. Rats were fasted for 24 hours before the last drug administration, then anesthetized within 1 hour of the last drug administration, and heart blood was collected.
(가) 혈청 사이토카인측정(A) Serum cytokine measurement
혈청을 분리한 후 -80 ℃ 냉동고에 분주하여 보관하였고, 각 사이토카인 측정 당일에 해동하여 각 ELISA 키트(CRP, TNFα, IL-6, IL-1β, PYGL)를 이용하여 정량하였다.After the serum was separated, it was stored in aliquots in a -80°C freezer, and on the day of each cytokine measurement, it was thawed and quantified using each ELISA kit (CRP, TNFα, IL-6, IL-1β, PYGL).
(나) 혈액 PYGL 활성 측정(B) Measurement of blood PYGL activity
글리코겐 포스포릴라제 활성 키트(Glycogen phosphorylase activity kit, BioVision)를 이용하여 혈액 PYGL 활성을 측정하였다.Blood PYGL activity was measured using a glycogen phosphorylase activity kit (BioVision).
(6) 대장 무게 측정(6) Measurement of colon weight
랫트의 대장을 적출하여 항문으로부터 5-6 츠 사이의 조직을 1 cm 길이로 잘라서 조직의 무게를 측정하였다.The large intestine of the rat was removed, the tissue 5-6 inches from the anus was cut into 1 cm long pieces, and the weight of the tissue was measured.
(7) 미엘로페록시다제(Myeloperoxidase, MPO) 측정(7) Myeloperoxidase (MPO) measurement
조직 내 호중구의 침윤한 정도를 확인하기 위해 호중구 정량하는 지표인 효소 MPO 양을 측정하였다. 대장 1 cm 크기를 차가운 PBS로 세척하고 무게를 측정하여 조직의 무게 10 mg당 용해 완충액(lysis buffer, pH7.4, 200 mM NaCl, 5 mM EDTA, 10 mM tris, 10% glycerin, 1 mM PMSF, 1 μg/mL leupeptin and 28 μg/mL aprotinin) 500 μL를 첨가한 후 Bead Blaster® D2400 homogenizer (Benchmark Scientific, NJ, USA)를 이용하여 균질화하였다. 균질화한 시료를 1500ｘg, 5분으로 2회 원심분리하여 상등액을 얻은 다음, 이 상등액 100 μL를 MPO ELISA 키트(HK210, Hycult Biotechnology, Netherlands)를 이용하여 측정하였다. 항-랫트 MPO 항체(Anti-rat MPO antibody)가 코팅된 96 well에 앞의 상등액을 100 μL 첨가하여 실온에서 1시간 반응시킨 후 세척 완충액으로 3회 세척하고 여기에 재구성 추적자 (reconstituted tracer)을 100 μl 첨가하여 실온에서 1시간 반응하고 3회 반복 세척한 다음, 스트렙타비딘-과산화효소 접합체(streptavidin-peroxidase conjugate)를 100 μL 첨가하고 실온에서 1시간 반응한 후, 세척하고 TMB 기질 용액(substrate solution)을 100 μL 가하여 반응 30분 후에 반응 종결액(stop solution) 100 μl로 정지시킨 다음 450 nm에서 흡광도를 측정하였다. MPO 활성도는 25 ℃에서 1분 동안 물에서 과산화수소 1 μM이 환원되는 수치를 의미하여 이것을 대장 조직 균질액 1 mL에 포함된 MPO 양으로 계산하였다.To confirm the degree of neutrophil infiltration within the tissue, the amount of the enzyme MPO, which is an indicator for quantifying neutrophils, was measured. A 1-cm section of the large intestine was washed with cold PBS, weighed, and added with lysis buffer (pH7.4, 200mM NaCl, 5mM EDTA, 10mM tris, 10% glycerin, 1mM PMSF) per 10mg of tissue weight. 500 μL (1 μg/mL leupeptin and 28 μg/mL aprotinin) was added and homogenized using a Bead Blaster® D2400 homogenizer (Benchmark Scientific, NJ, USA). The homogenized sample was centrifuged twice at 1500xg for 5 minutes to obtain a supernatant, and then 100 μL of this supernatant was measured using an MPO ELISA kit (HK210, Hycult Biotechnology, Netherlands). Add 100 μL of the above supernatant to 96 wells coated with anti-rat MPO antibody, react at room temperature for 1 hour, wash three times with washing buffer, and add 100 μL of reconstituted tracer to it. Add μl, react at room temperature for 1 hour, wash three times, add 100 μl of streptavidin-peroxidase conjugate, react for 1 hour at room temperature, wash, and TMB substrate solution. ) was added and the reaction was stopped 30 minutes later with 100 μl of stop solution, and then the absorbance was measured at 450 nm. MPO activity refers to the reduction level of 1 μM hydrogen peroxide in water for 1 minute at 25°C, and was calculated as the amount of MPO contained in 1 mL of colon tissue homogenate.
(8) 대장 조직 병리 관찰(8) Observation of colon tissue pathology
10% 중성 완충 포르말린(neutral buffered formalin)에 고정시킨 대장 조직의 H&E 염색 및 면역염색을 진행하였다.H&E staining and immunostaining of colon tissue fixed in 10% neutral buffered formalin were performed.
(가) H&E 염색 및 조직 손상 측정(A) H&E staining and tissue damage measurement
H&E 염색 후 현미경 하에서 관찰하여 점막 손상 및 회복 정도를 하기 표 2와 같이 점수화하였다.After H&E staining, it was observed under a microscope and the degree of mucosal damage and recovery was scored as shown in Table 2 below.
1. 궤양: 없음 (0); 경증(mild) 표면 (1); 보통 (2); 광범위한 전체 두께 (extensive-full thickness) (3)mucosal epithelium
1. Ulcer: None (0); Mild surface (1); Normal (2); extensive-full thickness (3)
2. 염증 세포 침윤물: 없음 (0); 경증(mild) (1); 보통 (2); 심함 (3)
3. 혈관성: 없음 (0); 경증(mild) (1); 보통 (2); 심함 (3)
4. 콜라겐 침착: 없음 (0); 경증(mild) (1); 보통 (2); 심함 (3)Lamina propria
2. Inflammatory cell infiltrate: none (0); mild (1); Normal (2); Severe (3)
3. Vascular: none (0); mild (1); Normal (2); Severe (3)
4. Collagen deposition: none (0); mild (1); Normal (2); Severe (3)
5. 염증세포 침윤물: 없음 (0); 경증(mild) (1); 보통 (2); 심함 (3)
6. 콜라겐 침착: 없음 (0); 경증(mild) (1); 보통 (2); 심함 (3)
7. 혈관성: 없음 (0); 경증(mild) (1); 보통 (2); 심함 (3)
8. 부종: 없음 (0); 경증(mild) (1); 보통 (2); 심함 (3)submucosa
5. Inflammatory cell infiltrate: none (0); mild (1); Normal (2); Severe (3)
6. Collagen deposition: none (0); mild (1); Normal (2); Severe (3)
7. Vascular: None (0); mild (1); Normal (2); Severe (3)
8. Edema: None (0); mild (1); Normal (2); Severe (3)
1. 궤양: 없음 (0); 경증(mild) 표면 (1); 보통 (2); 광범위한 전체 두께 (extensive-full thickness) (3)mucosal epithelium
1. Ulcer: None (0); Mild surface (1); Normal (2); extensive-full thickness (3)
(나) 대장 조직 사이토카인 발현 변화 측정 (ELISA 및 WB)(B) Measurement of changes in colonic tissue cytokine expression (ELISA and WB)
대장 조직을 갈아서 단백질을 추출하여 ELISA 및 WB (p-STAT1/3, STAT1/3, NF-κB, p-I-κB, I-κB, p-RIP1/3, RIP1/3, p-JAK1/2/3, TNFα, IL-6, IL-1β, IL-12, IL-17, NOS2)을 실시하였다.Colon tissue was ground and proteins were extracted by ELISA and WB (p-STAT1/3, STAT1/3, NF-κB, p-I-κB, I-κB, p-RIP1/3, RIP1/3, p-JAK1/2/ 3, TNFα, IL-6, IL-1β, IL-12, IL-17, NOS2) were performed.
(다) 대장 조직 염증신호 활성화(phosphorylation) 확인(C) Confirmation of phosphorylation of inflammatory signals in colon tissue
대장 조직 염증신호 활성화 정도는 WB으로 확인하였으며, p-STAT1/3 과 NF-kB의 시그널링(signaling)은 세포질(cytosol)과 핵(Nucleus) 분획 각각에 대해 확인하였다.The degree of colon tissue inflammatory signal activation was confirmed by WB, and signaling of p-STAT1/3 and NF-kB was confirmed in the cytosol and nuclear fractions, respectively.
(9) 대장 조직의 PYGL 활성 측정(9) Measurement of PYGL activity in colon tissue
글리코겐 포스포릴라제 활성 키트(Glycogen phosphorylase activity kit, Bio Visoln)을 이용하여 대장 조직의 PYGL 활성을 측정하였다.PYGL activity in colon tissue was measured using a glycogen phosphorylase activity kit (Bio Visoln).
2. 시험 결과2. Test results
(1) TNBS로 유도한 장염증 랫트 모델에서 약물 투여에 따른 체중변화(1) Body weight change following drug administration in a rat model of intestinal inflammation induced by TNBS
TNBS 처리 전의 몸무게를 기준으로 7일간 매일 일정 시간에 몸무게의 변화를 관찰한 결과, 도 2a에서 보는 바와 같이 정상 대조군의 체중은 계속해서 몸무게가 증가함을 보이고, TNBS 단독 투여군은 몸무게가 서서히 감소하여 투여 8일째에는 실험 시작 시점 대비 23%의 체중 감소가 확인되었다(도 2b). 각 약물투여군의 체중 회복률은 하기 표 3과 같다.As a result of observing changes in body weight at certain times every day for 7 days based on the body weight before TNBS treatment, as shown in Figure 2a, the body weight of the normal control group continued to increase, and the body weight of the group administered TNBS alone gradually decreased. On the 8th day of administration, a 23% weight loss compared to the start of the experiment was confirmed (Figure 2b). The weight recovery rate for each drug administration group is shown in Table 3 below.
질병 진행 정도(Disease Activity Index, DAI)로 확인한 결과, TNBS 단독 투여군의 경우 질병 진행 정도가 TNBS 투여 5일째에 최고에 달한 후 감소되는 경향을 보였다. 약물투여군의 경우 INV-101 10mg/kg 투여군의 경우 약물투여 3일째 이후부터 확연한 감소를 보였다(도 3). 반면 필고티닙 30 mg/kg, UC-205689 10 mg/kg, INV-101 1 mg/kg, INV-101 3mg/kg 의 경우는 서로간의 유의성은 없으나, TNBS 단독군에 비해 질병정도가 감소하였다.As a result of the disease progression (Disease Activity Index, DAI), in the group administered TNBS alone, the degree of disease progression peaked on the 5th day of TNBS administration and then tended to decrease. In the case of the drug administration group, the INV-101 10mg/kg administration group showed a clear decrease after the 3rd day of drug administration (Figure 3). On the other hand, there was no significance between filgotinib 30 mg/kg, UC-205689 10 mg/kg, INV-101 1 mg/kg, and INV-101 3mg/kg, but the disease severity decreased compared to the TNBS group alone. .
(2) 대장 조직 형태 및 무게 변화(2) Changes in colon tissue morphology and weight
(가) 대장의 형태학적 변화(A) Morphological changes in the large intestine
약물투여 7일 후에 대장을 적출하여 육안으로 살펴본 결과, TNBS를 단독으로 처리한 랫트의 대장은 대조군에 비하여 부종과 유착이 많이 관찰되었으며 충수돌기의 부종 또한 증가하였다. 또 일부에서는 염증이 심화되어 다른 장기 조직들과 유착현상이 나타났다(도 4). 약물을 처리한 군에서는 TNBS군에서 나타난 부종과 충혈이 억제되었으며 특히 INV-101의 경우 농도의존적 효과를 보였으며, INV-101 10 mg/kg 투여군의 경우는 정상대조군과 유사할 정도로 회복을 보였으며, 대조약물 필고티닙 30 mg/kg 또는 UC-205689 10 mg/kg보다 월등히 우수하였다.As a result of removing the large intestine 7 days after drug administration and examining it with the naked eye, the large intestine of rats treated with TNBS alone showed more edema and adhesions than the control group, and the swelling of the appendix also increased. In addition, in some cases, inflammation worsened and adhesion with other organ tissues appeared (Figure 4). In the drug-treated group, the edema and congestion that appeared in the TNBS group were suppressed, and in particular, INV-101 showed a concentration-dependent effect. The INV-101 10 mg/kg administered group showed recovery similar to the normal control group. , it was significantly superior to the control drug filgotinib 30 mg/kg or UC-205689 10 mg/kg.
(나) 대장 무게 변화(B) Change in colon weight
랫트의 대장을 적출하여 맹장(cecum)부터 직장까지 전체 길이의 무게를 측정한 결과, 비이클-처리 대조군에 비해 TNBS 단독 처리군의 경우 부종이 있으며 장의 무게가 유의적으로 증가하였고, 시험 물질을 투여한 그룹에서는 장의 무게가 TNBS 처리군에 비해 유의적으로 감소하였다. INV-101 10 mg/kg 투여 그룹의 효과가 가장 우수하였다(도 5). INV-101 10mg/kg 투여군의 경우는 회복률이 73.1%였으며, 대조약물 필고티닙 30 mg/kg의 회복률 55.1% 또는 UC-205689 10 mg/kg의 회복률 49.6%보다 월등히 우수하였다(표 4).The large intestine of the rat was removed and the weight of the entire length from the cecum to the rectum was measured. As a result, there was edema and the weight of the intestine was significantly increased in the TNBS-only treated group compared to the vehicle-treated control group, and the test substance was administered. In one group, intestinal weight was significantly reduced compared to the TNBS treatment group. The INV-101 10 mg/kg administration group had the best effect (Figure 5). In the case of the INV-101 10 mg/kg administration group, the recovery rate was 73.1%, which was significantly better than the control drug filgotinib 30 mg/kg recovery rate of 55.1% or UC-205689 10 mg/kg recovery rate of 49.6% (Table 4).
(3) 적출 대장의 조직 병리(3) Histopathology of extracted colon
(가) H&E 염색 및 조직 손상 정도(A) H&E staining and degree of tissue damage
장 조직의 손상 정도 및 약물 투여에 의한 회복 정도를 확인하기 위해 H&E 염색을 실시하고, 정상대조군에 비해 TNBS 단독 투여 군에서 현저한 장점막 손상을 확인하였으며, 시험 화합물 투여에 의해 장점막 회복을 확인할 수 있었으며, INV-101 10mg/kg의 개선 효과가 가장 우수하였다(도 6).H&E staining was performed to confirm the degree of damage to intestinal tissue and the degree of recovery by drug administration. Significant damage to the intestinal mucosa was confirmed in the group administered only TNBS compared to the normal control group. Recovery of the intestinal mucosa was confirmed by administration of the test compound. The improvement effect of INV-101 10mg/kg was the best (Figure 6).
표 2의 평가법에 의해 H&E로 염색된 조직의 손상의 정도를 측정하여 점수로 변환하여 분석한 결과, TNBS 단독 처리군에서는 점막조직의 궤양, 고유층 (Lamina propria)과 점막하층으로 염증세포의 침윤, 혈관분포, 섬유화(collagen fiber 축적) 및 부종성 변화를 나타내었으며, 화합물 투여에 의해 장조직 손상 정도가 완화되었다. INV-101은 용량의존적 효과를 보였으며, INV-101 10mg/kg 투여군의 효과가 대조약물 필고티닙 30 mg/kg 또는 UC-205689 10 mg/kg보다 월등히 우수하였다(도 7).As a result of measuring the degree of damage to the tissue stained with H&E using the evaluation method in Table 2 and converting it into a score, the TNBS-only treatment group showed ulcers in the mucosal tissue and infiltration of inflammatory cells into the lamina propria and submucosal layer. , vascular distribution, fibrosis (collagen fiber accumulation), and edematous changes were observed, and the extent of intestinal tissue damage was alleviated by compound administration. INV-101 showed a dose-dependent effect, and the effect of the INV-101 10 mg/kg group was significantly better than the control drug filgotinib 30 mg/kg or UC-205689 10 mg/kg (Figure 7).
(나) 대장 조직 사이토카인 발현 변화(B) Changes in colonic tissue cytokine expression
TNBS로 유도된 장염 마우스의 대장 조직에서 염증 사이토카인 발현(TNFα, IL-6, IL-1β, IL-12, IL-17, NOS2)이 현저히 증가되어 있으며, 화합물 투여에 의해 거의 감소함을 확인하였다. INV-101은 용량의존적 효과를 보였으며, INV-101 10mg/kg 투여군의 효과가 대조약물 필고티닙 30 mg/kg 또는 UC-205689 10 mg/kg보다 월등히 우수하였다(도 8).It was confirmed that the expression of inflammatory cytokines (TNFα, IL-6, IL-1β, IL-12, IL-17, NOS2) was significantly increased in the colonic tissue of mice with TNBS-induced enteritis, and was almost reduced by compound administration. did. INV-101 showed a dose-dependent effect, and the effect of the INV-101 10 mg/kg group was significantly better than the control drug filgotinib 30 mg/kg or UC-205689 10 mg/kg (Figure 8).
(다) 대장 조직 염증신호 활성화 정도(C) Degree of activation of inflammatory signals in colon tissue
대장 조직에서 TNBS에 의해 유도된 RIP-1/RIP-3의 인산화와 JAK2/JAK3의 인산화 및 STAT1/STAT3의 인산화가 화합물 투여에 의해 유의하게 억제됨을 확인하였다. INV-101은 용량의존적 효과를 보였으며, INV-101 10 mg/kg 투여군의 효과가 대조약물 필고티닙 30 mg/kg 또는 UC-205689 10 mg/kg보다 월등히 우수하였다(도 9a). 또한, TNBS에 의해 유도된 STAT3와 NF-κB가 핵으로 이동하는 것을 INV-101 10 mg/kg 투여에 의해 정상대조군 수준으로 억제됨을 확인하였다(도 9b).It was confirmed that phosphorylation of RIP-1/RIP-3, JAK2/JAK3, and STAT1/STAT3 induced by TNBS in colon tissue was significantly inhibited by compound administration. INV-101 showed a dose-dependent effect, and the effect of the INV-101 10 mg/kg group was significantly better than the control drug filgotinib 30 mg/kg or UC-205689 10 mg/kg (Figure 9a). In addition, it was confirmed that the movement of STAT3 and NF-κB induced by TNBS to the nucleus was inhibited to the level of the normal control by administration of 10 mg/kg of INV-101 (Figure 9b).
(4) 대장 조직 중 MPO 변화(4) MPO changes in colon tissue
MPO는 호중구에서 주로 발견되는 효소로서 조직에서 MPO의 존재는 호중구 침윤의 지표가 되며, 이는 곧 염증반응의 지표로서 염증성 대장염에 의한 장 손상 수치와 상관성을 나타낸다. MPO is an enzyme mainly found in neutrophils, and the presence of MPO in tissues is an indicator of neutrophil infiltration, which in turn is an indicator of inflammatory response and correlates with the level of intestinal damage caused by inflammatory colitis.
정상군에 비해 TNBS처리군에서 MPO 수치가 현저히 높게 나타났으며 화합물 투여에 의해 MPO 활성이 유의적으로 감소하였다. INV-101 10 mg/kg 투여군의 효과가 대조약물 필고티닙 30 mg/kg 또는 UC-205689 10 mg/kg보다 월등히 우수하였다(도 10).Compared to the normal group, MPO levels were significantly higher in the TNBS-treated group, and MPO activity was significantly decreased by compound administration. The effect of the INV-101 10 mg/kg administration group was significantly better than the control drug filgotinib 30 mg/kg or UC-205689 10 mg/kg (Figure 10).
(5) 혈액 분석(5) Blood analysis
(가) 혈청 사이토카인 측정(A) Serum cytokine measurement
혈중 사이토카인의 변화 정도를 각각의 엘라이자 키트(ELISA kit)를 이용하여 측정한 결과, TNBS 단독 투여군에서 증가된 사이토카인인 TNFα, IL-6, IL-1β, CRP이 화합물 처리에 의해 유의하게 억제됨을 확인하였다. 염증 사이토카인 억제 정도는 INV-101 10 mg/kg > INV-101 3 mg/kg = UC-205689 10 mg/kg > INV-101 1 mg/kg > 필고티닙 30 mg/kg 의 순으로 효과가 우수하였다(도 11a 내지 11d).As a result of measuring the degree of change in circulating cytokines using each ELISA kit, the increased cytokines TNFα, IL-6, IL-1β, and CRP in the TNBS-only group were significantly increased by compound treatment. It was confirmed that it was suppressed. The degree of inflammatory cytokine inhibition is in the following order: INV-101 10 mg/kg > INV-101 3 mg/kg = UC-205689 10 mg/kg > INV-101 1 mg/kg > Filgotinib 30 mg/kg. It was excellent (Figures 11a to 11d).
(나) 혈액 중 PYGL 분비 양 및 활성 변화(B) Changes in the amount and activity of PYGL secretion in the blood
TNBS로 유도된 장염 랫트의 혈액 중 PYGL의 양이 정상 대비 4배 정도 증가하였으며, 화합물 투여 그룹에서 유의하게 억제되었으며, INV-101 10 mg/kg 의 억제효과가 가장 강력하였으며, 나머지 그룹은 유사한 수준을 보였다(도 12a). 반면, TNBS 투여군에서 현저히 증가된 혈중 PYGL 효소 활성은 INV-101에 의해 용량의존적으로 억제되었으며, INV-101 10 mg/kg > INV-101 3 mg/kg > INV-101 1 mg/kg = UC-205689 10 mg/kg > 필고티닙 30 mg/kg의 순으로 효과가 우수하였다(도 12b). 특히 가장 강력한 억제활성을 보인 INV-101 10 mg/kg의 경우는 정상 대조군 수준으로 회복시킴을 확인하였다.The amount of PYGL in the blood of TNBS-induced enteritis rats increased by about 4 times compared to normal, and was significantly suppressed in the compound administration group. The inhibitory effect of INV-101 10 mg/kg was the strongest, and the remaining groups had similar levels. was shown (Figure 12a). On the other hand, the significantly increased blood PYGL enzyme activity in the TNBS administration group was suppressed by INV-101 in a dose-dependent manner, INV-101 10 mg/kg > INV-101 3 mg/kg > INV-101 1 mg/kg = UC- The effect was excellent in the order of 205689 10 mg/kg > filgotinib 30 mg/kg (FIG. 12b). In particular, INV-101 10 mg/kg, which showed the strongest inhibitory activity, was confirmed to restore the level to the normal control level.
(6) 대장 조직의 PYGL 활성 (6) PYGL activity in colon tissue
TNBS로 유도된 장염 랫트의 대장 조직의 PYGL의 양이 정상 대비 3배 정도 증가하였으며, 화합물 투여 그룹에서 유의하게 억제되었다. INV-101 10 mg/kg의 억제효과가 가장 강력하였으며, 나머지 그룹은 유사한 수준을 보였다. 반면, TNBS 투여군에서 현저히 증가된 대장 PYGL 효소 활성은 INV-101에 의해 용량의존적으로 억제되었으며, INV-101 10 mg/kg > INV-101 3 mg/kg > INV-101 1 mg/kg = UC-205689 10 mg/kg = 필고티닙 30 mg/kg의 순으로 효과가 우수하였다(도 13). 특히 가장 강력한 억제활성을 보인 INV-101 10 mg/kg의 경우는 정상 대조군 수준으로 회복시킴을 확인하였다.The amount of PYGL in the colonic tissue of TNBS-induced enteritis rats increased to about 3-fold compared to normal, and was significantly suppressed in the compound administration group. The inhibitory effect of INV-101 10 mg/kg was the strongest, and the remaining groups showed similar levels. On the other hand, the significantly increased colonic PYGL enzyme activity in the TNBS administration group was inhibited by INV-101 in a dose-dependent manner, INV-101 10 mg/kg > INV-101 3 mg/kg > INV-101 1 mg/kg = UC- The effect was excellent in the following order: 205689 10 mg/kg = filgotinib 30 mg/kg (Figure 13). In particular, INV-101 10 mg/kg, which showed the strongest inhibitory activity, was confirmed to restore the level to the normal control level.
상기 실험예 2의 결과에 의하면, 본 발명의 PYGL 저해제인 화합물 INV-101은 TNBS로 유도한 대장 염증 및 손상을 용량의존적으로 회복시켰으며, 혈중 및 대장 조직의 염증 사이토카인의 생성을 억제하고, 혈중PYGL의 증가를 억제할 뿐 아니라 증가된 PYGL 활성도 유의하게 억제하였다. 이러한 결과로부터 PYGL 저해제인 화합물 INV-101이 PYGL 활성 억제와 장염을 억제하는 효능이 매우 우수한 치료제 후보물질임이 확인되었다.According to the results of Experimental Example 2, compound INV-101, a PYGL inhibitor of the present invention, restored colonic inflammation and damage induced by TNBS in a dose-dependent manner, inhibited the production of inflammatory cytokines in the blood and colonic tissue, Not only did it suppress the increase in blood PYGL, but it also significantly suppressed the increased PYGL activity. From these results, it was confirmed that compound INV-101, a PYGL inhibitor, is a therapeutic candidate with excellent efficacy in inhibiting PYGL activity and enteritis.
또한, 상기 실험예 2의 결과에 따라, PYGL 저해능을 가지는 물질이 자가면역 질환의 예방 또는 치료에 유용하게 사용될 수 있음을 알 수 있으며, 기존약물을 대체하여 사용 가능함을 알 수 있다.In addition, according to the results of Experimental Example 2, it can be seen that substances having PYGL inhibition ability can be usefully used in the prevention or treatment of autoimmune diseases, and can be used as a replacement for existing drugs.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. 예를 들어, 단일형으로 설명되어 있는 각 구성 요소는 분산되어 실시될 수도 있으며, 마찬가지로 분산된 것으로 설명되어 있는 구성 요소들도 결합된 형태로 실시될 수 있다.The description of the present invention described above is for illustrative purposes, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential features of the present invention. will be. Therefore, the embodiments described above should be understood in all respects as illustrative and not restrictive. For example, each component described as single may be implemented in a distributed manner, and similarly, components described as distributed may also be implemented in a combined form.
본 발명의 범위는 후술하는 청구범위에 의하여 나타내어지며, 청구범위의 의미 및 범위 그리고 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.The scope of the present invention is indicated by the claims described below, and all changes or modified forms derived from the meaning and scope of the claims and their equivalent concepts should be construed as being included in the scope of the present invention.
Claims (7)
A pharmaceutical composition for preventing or treating autoimmune diseases, comprising a glycogen phosphorylase (PYGL) inhibitor as an active ingredient.
<화학식 1>
<화학식 2>
<화학식 3>
<화학식 4>
<화학식 5>
<화학식 6>
<화학식 7>
<화학식 8>
The pharmaceutical composition for preventing or treating autoimmune diseases according to claim 1, wherein the glycogen phosphorylase (PYGL) inhibitor is at least one selected from the group consisting of compounds represented by the following formulas 1 to 8.
<Formula 1>
<Formula 2>
<Formula 3>
<Formula 4>
<Formula 5>
<Formula 6>
<Formula 7>
<Formula 8>
The method of claim 1, wherein the autoimmune disease is inflammatory bowel disease, asthma, type 1 diabetes, rheumatoid arthritis, polymyalgia rheumatica, ankylosing spondylitis, psoriatic arthritis, psoriasis, eczema, scleroderma, vitiligo, multiple sclerosis, Interleukin-17 (IL-17)-induced dementia, peripheral neuritis, uveitis, polymyositis and dermatomyositis, autoimmune cytopenia, autoimmune myocarditis, atopic dermatitis, primary cirrhosis, dry eye, fibromyalgia, Goodficher syndrome, Autoimmune meningitis, Sjogren's syndrome, systemic lupus erythematosus, Addison's disease, alopecia areata, autoimmune hepatitis, autoimmune parotitis, dystrophic epidermolysis bullosa, epididymitis, glomerulonephritis, Graves' disease, celiac disease, Guillain-Barré syndrome, Hashimoto's disease , hemolytic anemia, myasthenia gravis, amyotrophic lateral sclerosis, pemphigus vulgaris, rheumatic fever, sarcoidosis, scleroderma, spondyloarthrosis, thyroiditis, vasculitis, vitiligo, myxedema, pernicious anemia, antiphospholipid syndrome, late solid organ transplantation and chronic rejection, and a pharmaceutical composition for preventing or treating autoimmune diseases, which is at least one selected from the group consisting of graft-versus-host disease.
The method of claim 3, wherein the inflammatory bowel disease is enteritis, colitis, ulcerative colitis, Crohn's disease, Crohn's sarcoma, irritable bowel syndrome, bleeding rectal ulcer, ileal pouchitis, peptic ulcer, intestinal Behcet's disease, and A pharmaceutical composition for the prevention or treatment of at least one autoimmune disease selected from the group consisting of gastritis.
The pharmaceutical composition for preventing or treating an autoimmune disease according to claim 3, wherein the inflammatory bowel disease is ulcerative colitis.
2) 글리코겐 포스포릴라제(PYGL)의 활성을 측정하는 단계; 및
3) 상기 글리코겐 포스포릴라제(PYGL)의 활성을 감소시키는 시험 물질을 자가면역 질환 치료제의 후보 물질로 결정하는 단계
를 포함하는, 자가면역 질환의 예방 또는 치료용 물질의 스크리닝 방법.
1) treating the test substance with glycogen phosphorylase (PYGL);
2) measuring the activity of glycogen phosphorylase (PYGL); and
3) Determining the test substance that reduces the activity of glycogen phosphorylase (PYGL) as a candidate for the treatment of autoimmune diseases
A screening method for a substance for preventing or treating autoimmune diseases, including.
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| KR102426921B1 (en) | 2019-09-24 | 2022-07-29 | 주식회사 이노보테라퓨틱스 | Heteroarylamidopyridinol derivatives and pharmaceutical composition for use in preventing or treating autoimmune diseases containing the same as an active ingredient |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR102426921B1 (en) | 2019-09-24 | 2022-07-29 | 주식회사 이노보테라퓨틱스 | Heteroarylamidopyridinol derivatives and pharmaceutical composition for use in preventing or treating autoimmune diseases containing the same as an active ingredient |
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