KR20220132477A - Novel chemical compound and composition for preventing or treating degenerative brain disease using the same - Google Patents
Novel chemical compound and composition for preventing or treating degenerative brain disease using the same Download PDFInfo
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- KR20220132477A KR20220132477A KR1020220036316A KR20220036316A KR20220132477A KR 20220132477 A KR20220132477 A KR 20220132477A KR 1020220036316 A KR1020220036316 A KR 1020220036316A KR 20220036316 A KR20220036316 A KR 20220036316A KR 20220132477 A KR20220132477 A KR 20220132477A
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- disease
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- degenerative brain
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Abstract
Description
본 발명은 신규한 화합물 또는 이의 허용 가능한 염; 이를 포함하는 퇴행성 뇌질환 예방 또는 치료용 약학적 조성물, 식품 조성물, 의약외품 조성물, 사료 조성물, 및 상기 약학적 조성물을 이용한 퇴행성 뇌질환 예방 또는 치료 방법에 관한 것이다.The present invention relates to a novel compound or an acceptable salt thereof; It relates to a pharmaceutical composition for preventing or treating degenerative brain disease, a food composition, a quasi-drug composition, a feed composition, and a method for preventing or treating degenerative brain disease using the pharmaceutical composition, including the same.
최근 고령화 사회에 진입하면서, 고령화와 동반되는 대표적인 질환인 퇴행성 뇌질환에 대한 관심이 증가하고 있다. 퇴행성 뇌질환의 대표적인 예로 알츠하이머성 치매(Alzheimer's dementia) 예방 및 치료 시장도 성장하여 2018년 1조 달러에서 2030년에는 2조 달러의 시장에 달할 것으로 전망되고 있다.Recently, as we enter an aging society, interest in degenerative brain disease, which is a representative disease accompanying aging, is increasing. As a representative example of degenerative brain disease, the Alzheimer's dementia prevention and treatment market is also growing and is expected to reach $2 trillion in 2030 from $1 trillion in 2018.
그러나, 1900년도 초반에 최초로 알려진 이후로, 퇴행성 뇌질환의 일종인 치매의 가장 흔한 형태로서 연구되어온 알츠하이머 조차도, 아직까지도 현대 의학에서도 치료할 수 없는 질병으로 알려져 있으며, 발병 후 증상이 악화되고 결과적으로 죽음에 이르는 질병으로 인식되어 있다. 일 예로, 알츠하이머 치료를 위해 아세틸콜린분해효소 저해제 등의 약물이 사용되었으나(Francis, Paul T. (2005). The Interplay of Neurotransmitters in Alzheimer's Disease. CNS Spectrums, 10(S18), 6-9.), 이는 증상 완화일 뿐이며 현재까지도 치매의 근본적인 치료법은 알려지지 않은 실정이다.However, even Alzheimer's, which has been studied as the most common form of dementia, a type of degenerative brain disease, since it was first known in the early 1900s, is still known as a disease that cannot be cured even in modern medicine, and symptoms worsen after onset and result in death. recognized as a disease leading to For example, drugs such as acetylcholinease inhibitors have been used for the treatment of Alzheimer's (Francis, Paul T. (2005). The Interplay of Neurotransmitters in Alzheimer's Disease. CNS Spectrums, 10(S18), 6-9.), This is only symptom relief, and the fundamental treatment for dementia is still unknown.
이러한 배경 하에서, 기존에 연구된 퇴행성 뇌질환 치료제의 타겟에서 벗어나, 후성 유전학과 관련된 단백질을 타겟으로 하여, 퇴행성 뇌질환 예방 또는 치료를 위한 신규한 화합물을 발굴함으로써 본 발명을 완성하였다.Under this background, the present invention was completed by finding a novel compound for preventing or treating degenerative brain disease by targeting a protein related to epigenetics, away from the target of the previously studied degenerative brain disease therapeutic agent.
본 발명의 하나의 목적은 1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아 (1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea) 화합물 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다.One object of the present invention is 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea (1-phenyl-3-{6-[3-(trifluoromethyl) )phenoxy]pyridin-3-yl}urea) compound or a pharmaceutically acceptable salt thereof.
본 발명의 다른 하나의 목적은 상기 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 뇌질환 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating degenerative brain disease comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 하나의 목적은 상기 화합물 또는 이의 식품학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 뇌질환 예방 또는 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for preventing or improving degenerative brain disease comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 하나의 목적은 상기 화합물 또는 이의 의약외품학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 뇌질환 예방 또는 개선용 의약외품 조성물을 제공하는 것이다.Another object of the present invention is to provide a quasi-drug composition for preventing or improving degenerative brain disease comprising the compound or a quasi-pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 하나의 목적은 상기 화합물 또는 이의 사료학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 뇌질환 예방 또는 개선용 사료 조성물을 제공하는 것이다.Another object of the present invention is to provide a feed composition for preventing or improving degenerative brain disease, comprising the compound or a fodder acceptable salt thereof as an active ingredient.
본 발명의 또 다른 하나의 목적은 상기 약학적 조성물을 이용한 퇴행성 뇌질환 예방 또는 치료 방법을 제공하는 것이다. Another object of the present invention is to provide a method for preventing or treating degenerative brain disease using the pharmaceutical composition.
본 발명의 또 다른 하나의 목적은 상기 식품, 의약외품, 또는 사료 조성물을 이용한 퇴행성 뇌질환 예방 또는 개선 방법을 제공하는 것이다.Another object of the present invention is to provide a method for preventing or improving degenerative brain disease using the food, quasi-drug, or feed composition.
이하, 본 발명 내용에 대하여 구체적으로 설명하면 다음과 같다. 한편, 본 발명에서 개시한 일 양태의 설명 및 실시형태는 공통된 사항에 대하여 다른 양태의 설명 및 실시 형태에도 적용될 수 있다. 또한, 본 발명에서 개시된 다양한 요소들의 모든 조합이 본 발명의 범주에 속한다. 더불어, 하기 기술된 구체적인 서술에 의하여 본 발명의 범주가 제한된다고 볼 수 없다.Hereinafter, the content of the present invention will be described in detail as follows. On the other hand, descriptions and embodiments of one aspect disclosed in the present invention may be applied to descriptions and embodiments of other aspects with respect to common matters. Also, all combinations of the various elements disclosed herein are within the scope of the present invention. In addition, it cannot be seen that the scope of the present invention is limited by the specific descriptions described below.
본 발명의 일 양태는 1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아 (1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea) 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다.One aspect of the present invention is 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea (1-phenyl-3-{6-[3-(trifluoromethyl) phenoxy]pyridin-3-yl}urea) compound or a pharmaceutically acceptable salt thereof.
구체적으로, 상기 화합물은 하기 화학식 1로 표시되는 화합물일 수 있다.Specifically, the compound may be a compound represented by the following formula (1).
일 구현 예로, 상기 화합물은 신규한 MeCP2(Methyl-CpG-binding protein 2) 저해제일 수 있으나, 이에 제한되지 않는다.In one embodiment, the compound may be a novel Methyl-CpG-binding protein 2 (MeCP2) inhibitor, but is not limited thereto.
본 발명자들은 상기 신규한 MeCP2 저해제 화합물을 최초로 발굴하였으며, 상기 화합물이 퇴행성 뇌질환을 치료할 수 있음을 최초로 규명한 것에 기술적 의의가 있다.The present inventors discovered the novel MeCP2 inhibitor compound for the first time, and it has technical significance in that it was first identified that the compound can treat degenerative brain disease.
본 발명의 또 다른 하나의 양태는 1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 MeCP2 저해용 조성물을 제공한다.Another embodiment of the present invention is MeCP2 comprising 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea compound or a pharmaceutically acceptable salt thereof An inhibitory composition is provided.
본 발명의 또 다른 하나의 양태는 1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 뇌질환 예방 또는 치료용 약학적 조성물을 제공한다.Another aspect of the present invention is a 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea compound or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a pharmaceutical composition for preventing or treating degenerative brain disease, including.
본 발명에서 "퇴행성 뇌질환(degenerative brain disease)"은 노화에 따라 발생할 수 있는 뇌 질환을 의미하며, 파킨슨 병, 알츠하이머성 치매, 노인성 치매, 기억 장애, 및 기억상실로 이루어진 군으로부터 선택되는 어느 하나일 수 있고, 본 발명의 목적상, 상기 퇴행성 뇌질환은 알츠하이머성 치매일 수 있으나, 이에 제한되지 않는다.In the present invention, "degenerative brain disease (degenerative brain disease)" refers to a brain disease that can occur with aging, and any one selected from the group consisting of Parkinson's disease, Alzheimer's disease, senile dementia, memory impairment, and memory loss may be, and for the purposes of the present invention, the degenerative brain disease may be Alzheimer's dementia, but is not limited thereto.
본 발명에서 "알츠하이머성 치매(Alzheimer's dementia, Alzheimer's disease)"는 뇌세포의 점진적인 퇴행성 변화로 인하여 뇌기능을 저하시키는 퇴행성 뇌질환을 의미하며, 알츠하이머병 및 알츠하이머와 혼용될 수 있다. 알츠하이머병은 치매의 대표적인 원인질환으로서 전체 치매의 절반 이상을 차지하는 가장 흔한 퇴행성 뇌질환이며, 신경전달물질인 아세틸콜린(acetylcholine)이 감소하면서 발병할 수 있고, 뇌세포의 점진적인 퇴행성 변화 및 뇌조직 감소로 인하여 기억력, 언어능력, 판단력, 및/또는 방향감각 등이 저하시킬 수 있다. 상기 알츠하이머성 치매는 진행 정도, 지적 능력 손상, 기억력 감퇴, 언어능력 약화, 및 판단 장애 등의 정도에 따라 초기(early stage, mild stage) 및 중기(midstage, moderate stage) 또는 말기(late stage, severe stage)로 구분될 수 있다. 본 발명에서 알츠하이머성 치매는 초기 알츠하이머성 치매, 중기 알츠하이머성 치매, 및 말기 알츠하이머성 치매를 모두 포함할 수 있으며, 구체적으로, 중기 알츠하이머성 치매 또는 말기 알츠하이머성 치매일 수 있고, 보다 구체적으로, 말기 알츠하이머성 치매일 수 있으나, 이에 제한되지 않는다.In the present invention, "Alzheimer's dementia (Alzheimer's disease)" refers to a degenerative brain disease that reduces brain function due to gradual degenerative changes in brain cells, and may be used interchangeably with Alzheimer's disease and Alzheimer's disease. Alzheimer's disease is the most common degenerative brain disease that accounts for more than half of all dementias as a representative causative disease of dementia. As a result, memory, language ability, judgment, and/or sense of direction may be impaired. The Alzheimer's dementia is early stage (early stage, mild stage) and intermediate stage (midstage, moderate stage) or late stage (late stage, severe stage) can be distinguished. In the present invention, Alzheimer's dementia may include all of early Alzheimer's dementia, middle-stage Alzheimer's dementia, and late-stage Alzheimer's dementia, specifically, middle-stage Alzheimer's dementia or late-stage Alzheimer's dementia, and more specifically, late stage Alzheimer's dementia It may be Alzheimer's dementia, but is not limited thereto.
알츠하이머성 치매 치료제의 타깃으로 아밀로이드 B(amyloid B) 및 타우(Tau) 단백질 등이 연구된 바 있으나, 본 발명에서는 후성유전학과 관련된 단백질인 MeCP2를 타겟으로 하여, 알츠하이머성 치매 예방 또는 치료를 위한 신규한 화합물을 발굴하였다. 본 발명의 신규한 화합물인 1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아 또는 이의 약학적으로 허용 가능한 염이 공지된 알츠하이머성 치매 치료제보다도 더 우수한 알츠하이머성 치매 치료 효과를 나타낼 수 있음을 최초로 규명하였다는 데 의의가 있다. Although amyloid B and Tau protein have been studied as targets for the treatment of Alzheimer's dementia, in the present invention, MeCP2, a protein related to epigenetics, is targeted, and a novel method for preventing or treating Alzheimer's dementia A compound was discovered. The novel compound of the present invention, 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea or a pharmaceutically acceptable salt thereof, is a known therapeutic agent for Alzheimer's disease It is significant in that it was first identified that it can exhibit a better treatment effect for Alzheimer's disease than that.
또한, 본 발명의 1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아 화합물 또는 이의 약학적으로 허용 가능한 염은 초기, 중기, 및/또는 말기 알츠하이머성 치매를 치료하는 것일 수 있으며, 구체적으로, 중기 또는 말기 알츠하이머성 치매, 보다 구체적으로, 말기 알츠하이머성 치매를 예방 또는 치료하는 것일 수 있으나, 이에 제한되지 않는다.In addition, the 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea compound of the present invention or a pharmaceutically acceptable salt thereof is in the initial, intermediate, and/or It may be to treat late-stage Alzheimer's dementia, specifically, it may be to prevent or treat late-stage or late-stage Alzheimer's dementia, more specifically, late-stage Alzheimer's dementia, but is not limited thereto.
본 발명에서 "MeCP2(Methyl-CpG-binding protein 2)"는 메틸화 프로모터의 전사를 특이적으로 억제하는 단백질을 의미한다.In the present invention, "MeCP2 (Methyl-CpG-binding protein 2)" refers to a protein that specifically inhibits transcription of a methylation promoter.
본 발명에서 "MeCP2 저해제"는 상기 MeCP2의 발현 또는 활성을 저해, 감소, 불활성화, 또는 억제하는 제제를 의미한다. 구체적으로, MeCP2 단백질 또는 MeCP2 단백질을 코딩하는 폴리뉴클레오티드, 이의 유래 전사체의 생산 및 발현을 감소시킬 수 있는 모든 물질을 포함한다. 상기 제제는 유전자에 결합하여 그 발현을 전사 수준에서 억제하는 전사인자; 전사되어 생성된 전사체에 결합하여 전사체를 분해하는 miRNA, siRNA, shRNA 등의 RNA; 발현된 단백질과 결합할 수 있는 항체, 압타머, 안타고니스트, 또는 화합물 등을 포함할 수 있으나, 이에 제한되지 않는다. 본 발명의 신규한 MeCP2 저해제 화합물은 다른 MeCP2 저해제와 함께 사용될 수 있다.In the present invention, "MeCP2 inhibitor" refers to an agent that inhibits, reduces, inactivates, or inhibits the expression or activity of MeCP2. Specifically, it includes all substances capable of reducing the production and expression of MeCP2 protein or a polynucleotide encoding MeCP2 protein, and transcripts derived therefrom. The agent may include a transcription factor that binds to a gene and inhibits its expression at the transcriptional level; RNA such as miRNA, siRNA, and shRNA that binds to the transcribed transcript and degrades the transcript; It may include, but is not limited to, an antibody, aptamer, antagonist, or compound capable of binding to the expressed protein. The novel MeCP2 inhibitor compounds of the present invention may be used in combination with other MeCP2 inhibitors.
본 발명에서 "siRNA(short interfering RNA)"는 전사 과정 이후에 특정 mRNA의 활성을 저하시켜 특정 유전자의 발현을 방해하는, 20 내지 25 염기쌍으로 이루어진 이중가닥 RNA를 의미한다. In the present invention, "siRNA (short interfering RNA)" refers to a double-stranded RNA consisting of 20 to 25 base pairs that inhibits the expression of a specific gene by reducing the activity of a specific mRNA after the transcription process.
본 발명에서 "항체"는 단백질 또는 펩티드 분자의 항원성 부위에 특이적으로 결합할 수 있는 물질을 의미하는 것으로, 이는 당업계에 공지된 통상적인 방법에 의해 제조될 수 있다. 상기 항체의 형태는 특별히 제한되지 않는바, 폴리클로날 항체, 모노클로날 항체 및 항원 결합성을 갖는 것이면 그것의 일부도 본 발명의 항체에 포함되고, 모든 면역글로불린 항체뿐만 아니라 인간화 항체 등의 특수한 항체를 포함할 수 있다. In the present invention, "antibody" refers to a substance capable of specifically binding to an antigenic site of a protein or peptide molecule, which may be prepared by a conventional method known in the art. The form of the antibody is not particularly limited, and as long as it has polyclonal antibody, monoclonal antibody, and antigen-binding property, a part thereof is also included in the antibody of the present invention, and not only all immunoglobulin antibodies but also special antibodies such as humanized antibodies may include antibodies.
본 발명에서 "압타머(aptamer)"는 표적 물질에 대한 결합 활성을 갖는 핵산 분자를 의미하는 것으로, RNA, DNA 및 변형된(modified) 핵산 또는 이들의 혼합물일 수 있으며, 직쇄상 또는 환상의 형태일 수 있으나 이에 제한되지 않는다. In the present invention, "aptamer (aptamer)" refers to a nucleic acid molecule having binding activity to a target substance, and may be RNA, DNA, and a modified nucleic acid or a mixture thereof, and has a linear or cyclic form. may be, but is not limited thereto.
본 발명에서 "안타고니스트(antagonist)"는 수용체의 생물학적 활성을 직접 또는 간접적으로 감소시킬 수 있는 물질을 의미하며, 수용체의 리간드와 함께 사용하는 경우에 상기 리간드의 작용을 감소시킬 수 있는 분자를 포함하나, 이에 제한되지 않는다. 본 발명의 목적상 상기 RNA, 항체, 압타머, 안타고니스트 등은 안타고니스트는 MeCP2 저해할 수 있는 것인 한, 제한 없이 포함될 수 있다. In the present invention, "antagonist" refers to a substance that can directly or indirectly reduce the biological activity of a receptor, and includes molecules that can reduce the action of the ligand when used together with a ligand of a receptor. , but not limited thereto. For the purposes of the present invention, the RNA, antibody, aptamer, antagonist, etc. may be included without limitation as long as the antagonist is capable of inhibiting MeCP2.
일 구현예로, 본 발명자들은 퇴행성 뇌질환 예방 또는 치료를 위하여, 신규한 화합물을 발굴하였다. In one embodiment, the present inventors have discovered a novel compound for the prevention or treatment of degenerative brain disease.
하나의 구체 예로, 상기 MeCP2 저해제는 1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아 화합물 또는 이의 약학적으로 허용 가능한 염일 수 있으나, 이에 제한되지 않는다. 구체적으로, 상기 화합물은 상기 화학식 1로 표시되는 것일 수 있다. In one embodiment, the MeCP2 inhibitor may be a 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea compound or a pharmaceutically acceptable salt thereof, not limited Specifically, the compound may be represented by
일 구현예로, 본 발명자들은 상기 화합물을 인공지능(Artificial Intelligence: AI) 딥러닝 기술(ensECBS)을 이용한 스크리닝 방법을 통해 발굴하였으며, 상기 ensECBS을 통해 상기 화합물을 발굴하였고, 그러나, 본 발명의 목적상 상기 화합물은 이의 명칭 및/또는 구조가 동일하다면 이의 발굴 방법 등에 제한되지 않는다.In one embodiment, the present inventors discovered the compound through a screening method using artificial intelligence (AI) deep learning technology (ensECBS), and discovered the compound through the ensECBS, however, the purpose of the present invention Phase the compound is not limited to its excavation method, etc. as long as its name and/or structure are the same.
본 발명의 일 실시예에서는 상기 화합물이 MeCP2를 효과적으로 억제함을 확인하였으며, 퇴행성 뇌질환 치료 효과가 우수함을 확인하였다.In one embodiment of the present invention, it was confirmed that the compound effectively inhibited MeCP2, and it was confirmed that the effect of treating degenerative brain disease was excellent.
본 발명의 용어, "약학적으로 허용 가능한 염"은 양이온과 음이온이 정전기적 인력에 의해 결합하고 있는 물질인 염 중에서도 약제학적으로 사용될 수 있는 형태의 염을 의미하며, 통상적으로 금속염, 유기염기와의 염, 무기산과의 염, 유기산과의 염, 염기성 또는 산성 아미노산과의 염 등이 될 수 있다. 예를 들어, 금속염으로는 알칼리 금속염(나트륨염, 칼륨염 등), 알칼리 토금속염(칼슘염, 마그네슘염, 바륨염 등), 알루미늄염 등이 될 수 있고; 유기염기와의 염으로는 트리에틸아민, 피리딘, 피콜린, 2,6-루티딘, 에탄올아민, 디에탄올아민, 트리에탄올아민, 시클로헥실아민, 디시클로헥실아민, N,N-디벤질에틸렌디아민 등과의 염이 될 수 있으며; 무기산과의 염으로는 염산, 브롬화수소산, 질산, 황산, 인산 등과의 염이 될 수 있고; 유기산과의 염으로는 포름산, 아세트산, 트리플루오로아세트산, 프탈산, 푸마르산, 옥살산, 타르타르산, 말레인산, 시트르산, 숙신산, 메탄술폰산, 벤젠술폰산, p-톨루엔술폰산 등과의 염이 될 수 있으며; 염기성 아미노산과의 염으로는 아르기닌, 라이신, 오르니틴 등과의 염이 될 수 있고; 산성 아미노산과의 염으로는 아스파르트산, 글루탐산 등과의 염이 될 수 있다.As used herein, the term “pharmaceutically acceptable salt” refers to a salt in a form that can be used pharmaceutically among salts in which a cation and anion are bonded by electrostatic attraction, and is usually a metal salt, an organic base and salts, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. For example, the metal salt may be an alkali metal salt (sodium salt, potassium salt, etc.), alkaline earth metal salt (calcium salt, magnesium salt, barium salt, etc.), an aluminum salt or the like; Salts with organic bases include triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine salts with, etc.; salts with inorganic acids may be salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like; Salts with organic acids may be salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like; Salts with basic amino acids may be salts with arginine, lysine, ornithine and the like; The salt with an acidic amino acid may be a salt with aspartic acid, glutamic acid, or the like.
본 발명의 약학적 조성물은 조성물 총 중량에 대하여 이의 약학적으로 허용 가능한 염을 0.01 내지 80%, 구체적으로 0.01 내지 70%, 더욱 구체적으로 0.01 내지 60 중량%로 포함할 수 있으나, 퇴행성 뇌질환, 이의 관련 질환, 및 관련 증상의 예방 또는 치료 효과를 나타내는 한, 이에 제한되지 않는다.The pharmaceutical composition of the present invention may contain 0.01 to 80%, specifically 0.01 to 70%, more specifically 0.01 to 60% by weight of a pharmaceutically acceptable salt thereof based on the total weight of the composition, but degenerative brain disease, It is not limited thereto as long as it exhibits a preventive or therapeutic effect on its related diseases and related symptoms.
본 발명의 약학적 조성물은 약학적으로 허용되는 담체, 부형제 또는 희석제를 추가로 포함하는 것일 수 있다.The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier, excipient or diluent.
상기 "담체"는 생물체를 자극하지 않으면서, 주입되는 화합물의 생물학적 활성 및 특성을 저해하지 않는 담체를 의미할 수 있으며, 구체적으로, 비자연적 담체(non-naturally occuring carrier)를 포함할 수 있다. 본 발명에 사용 가능한 상기 담체의 종류는 특별히 제한되지 아니하며 당해 기술 분야에서 통상적으로 사용되고 약학적으로 허용되는 담체라면 어느 것이든 사용할 수 있다. 상기 담체의 비제한적인 예로는, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사 용액, 덱스트로스 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 등을 들 수 있다. 이들은 단독으로 사용되거나 2 종 이상을 혼합하여 사용될 수 있다.The "carrier" may refer to a carrier that does not inhibit the biological activity and properties of the injected compound without irritating the organism, and specifically, may include a non-naturally occurring carrier. The type of carrier usable in the present invention is not particularly limited, and any carrier commonly used in the art and pharmaceutically acceptable may be used. Non-limiting examples of the carrier include saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and the like. These may be used alone or may be used in combination of two or more.
상기 조성물은 경구 또는 비경구의 여러 가지 제형일 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다.The composition may be in various oral or parenteral formulations. In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used.
상세하게는, 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 화합물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트, 수크로오스, 락토오스, 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 액체 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 오일, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로골, 트윈 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.Specifically, solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient to the compound, for example, starch, calcium carbonate, sucrose, lactose. , gelatin, etc. may be mixed and prepared. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid formulations for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, Witepsol, Macrogol, Tween 61, cacao butter, laurin fat, glycerogelatin, etc. may be used.
구체적으로, 상기 약학적 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 주사제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 상기 약학적 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 약학적 조성물의 제조에 통상적으로 사용되는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구 투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calciumcarbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 통상적으로 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예컨대 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함될 수 있다. 또한, 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Specifically, the pharmaceutical composition is formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, injections, suppositories, and sterile injection solutions, respectively, according to conventional methods. can be used for Carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, it may be prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant commonly used in the preparation of a pharmaceutical composition. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient, for example, starch, calcium carbonate, sucrose, or lactose ( lactose), gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid formulations for oral use include suspensions, internal solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. may be included. Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. In addition, as the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. As a base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
본 발명의 약학적 조성물에 포함된 상기 담체, 부형제 또는 희석제의 함량은 특별히 이에 제한되지 않으나, 최종 조성물 총중량을 기준으로 0.0001 내지 50 중량%, 보다 바람직하게는 0.01 내지 10 중량%의 함량으로 포함할 수 있으나, 이에 제한되지 않는다.The content of the carrier, excipient or diluent included in the pharmaceutical composition of the present invention is not particularly limited thereto, but is based on the total weight of the final composition in an amount of 0.0001 to 50% by weight, more preferably 0.01 to 10% by weight. can, but is not limited thereto.
상기 본 발명의 약학적 조성물은 약학적으로 유효한 양을 포함할 수 있다. 상기 "약학적으로 유효한 양"이란 의학적 치료 또는 예방에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료 또는 예방하기에 충분한 양을 의미하며, 유효 용량 수준은 구체적 조성물, 질환의 중증도, 약물의 활성, 환자의 연령, 체중, 건강, 성별, 식이, 환자의 약물에 대한 민감도, 사용된 본 발명 조성물의 투여 시간, 투여 경로 및 배출 비율 치료기간, 조성물의 분비율, 사용된 본 발명의 조성물과 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. The pharmaceutical composition of the present invention may contain a pharmaceutically effective amount. The "pharmaceutically effective amount" means an amount sufficient to treat or prevent a disease at a reasonable benefit/risk ratio applicable to medical treatment or prevention, and the effective dose level is determined by the specific composition, the severity of the disease, the activity of the drug, Patient's age, weight, health, sex, diet, patient's sensitivity to drug, administration time of the present composition used, administration route and excretion rate treatment period, secretion rate of the composition, combination with the composition of the present invention used or It may depend on factors including drugs used concurrently and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times.
본 발명의 약학적 조성물의 투여량은 사용목적, 질환의 정도, 진행경과, 환자의 연령, 체중, 성별, 또는 유효성분으로서 사용되는 물질의 종류 등을 고려하여 당업자가 결정할 수 있다. 일반적으로 0.001 내지 1000 mg/kg의 양, 구체적으로는 0.05 내지 200 mg/kg, 보다 구체적으로는 0.1 내지 100 mg/kg의 양을 일일 1회 내지 수회로 나누어 투여할 수 있다. 본 발명의 약학 조성물은 매일 투여 또는 간헐적으로 투여할 수 있고, 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다.The dosage of the pharmaceutical composition of the present invention can be determined by those skilled in the art in consideration of the purpose of use, the degree of disease, the progress of the patient, the age, weight, sex, or the type of material used as an active ingredient. In general, an amount of 0.001 to 1000 mg/kg, specifically 0.05 to 200 mg/kg, and more specifically, an amount of 0.1 to 100 mg/kg may be administered once a day or divided into several times a day. The pharmaceutical composition of the present invention may be administered daily or intermittently, and it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects in consideration of all of the above factors, and can be easily determined by those skilled in the art. .
본 발명의 약학적 조성물은 당업계에 공지된 퇴행성 뇌질환 예방 또는 치료용 물질 및 이들의 유도체와 각종 식물 추출물로 구성되는 군으로부터 선택되는 1종 이상의 성분을 추가로 포함할 수 있다. 또한, 추가 성분은 전체 조성물 중량에 대하여 0.0001 중량% 내지 10 중량%로 포함될 수 있을 것이며, 상기 함량 범위는 안전성, 본 발명 조성물의 제형화 시의 용이성 등의 요건에 따라 조절될 수 있을 것이다.The pharmaceutical composition of the present invention may further include one or more components selected from the group consisting of substances for preventing or treating degenerative brain diseases known in the art, derivatives thereof, and various plant extracts. In addition, the additional component may be included in an amount of 0.0001 wt% to 10 wt% based on the total weight of the composition, and the content range may be adjusted according to requirements such as safety and ease of formulation of the composition of the present invention.
본 발명의 또 다른 하나의 양태는 본 발명의 약학적 조성물을 개체에 투여하는 단계를 포함하는 퇴행성 뇌질환 예방 또는 치료 방법을 제공한다.Another aspect of the present invention provides a method for preventing or treating degenerative brain disease comprising administering the pharmaceutical composition of the present invention to an individual.
상기 약학적 조성물 및 퇴행성 뇌질환 등은 다른 양태에서 기재된 바와 같다.The pharmaceutical composition and degenerative brain disease are the same as described in other embodiments.
본 발명에서 "개체"는 상기 퇴행성 뇌질환이 발병될 가능성이 있거나 발병된 인간을 포함한 쥐, 생쥐, 가축(예를 들어, 소, 말 등), 및 반려동물(예를 들어, 개, 고양이 등) 등을 의미한다. 구체적으로, 상기 개체는 인간을 포함한 포유동물일 수 있다.In the present invention, "individual" means rats, mice, livestock (eg, cattle, horses, etc.), including humans, and companion animals (eg, dogs, cats, etc.) ), etc. Specifically, the subject may be a mammal including a human.
본 발명의 용어 "투여"는 어떠한 적절한 방법으로 개체에게 본 발명의 조성물을 도입하는 것을 의미하며, 조성물의 투여 경로는 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있다. 구체적으로, 비경구 투여 시 비강 투여, 피부 외용 또는 복강 내 주사, 직장 내 주사, 피하주사, 정맥 내 주사, 근육 내 주사 또는 흉부 내 주사 등의 주입방식을 선택할 수 있다. 상기 비강 투여는 비강 내 흡입 및 비강 내 주사 등의 방식을 선택할 수 있으나, 이에 제한되지 않는다. 또한, 상기 조성물은 약학적으로 유효한 양으로 투여할 수 있다. The term "administration" of the present invention means introducing the composition of the present invention to an individual by any suitable method, and the administration route of the composition may be administered through various routes, either oral or parenteral. Specifically, for parenteral administration, an injection method such as nasal administration, external skin application or intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection may be selected. For the nasal administration, methods such as intranasal inhalation and intranasal injection may be selected, but the present invention is not limited thereto. In addition, the composition may be administered in a pharmaceutically effective amount.
본 발명에서 용어, "예방"은 본 발명의 조성물의 투여로 퇴행성 뇌질환의 발병 또는 진행을 억제 또는 지연시키는 모든 행위를 의미한다.As used herein, the term "prevention" refers to any action that inhibits or delays the onset or progression of degenerative brain disease by administration of the composition of the present invention.
본 발명에서 용어, "치료"는 치료하고자 하는 대상체 또는 세포의 천연 과정을 변경시키기 위해 임상적으로 개입하는 것을 지칭하고, 이는 임상 병리 상태가 진행되는 동안 또는 이를 예방하기 위해 수행할 수 있다. 목적하는 치료 효과에는 질병의 발생 또는 재발을 예방하고, 증상을 완화시키며, 질병에 따른 모든 직접 또는 간접적인 병리학적 결과를 저하시키며, 질병 진행 속도를 감소시키며, 질병 상태를 경감 또는 일시적 완화시키며, 차도시키거나 예후를 개선시키는 것이 포함된다. 구체적으로 본 발명의 조성물의 투여로 퇴행성 뇌질환 또는 이의 관련 증상을 호전시키는 모든 행위를 포함한다. As used herein, the term "treatment" refers to clinical intervention to alter the natural process of a subject or cell to be treated, which can be performed during the progression of a clinical pathology or to prevent it. The desired therapeutic effect includes preventing the occurrence or recurrence of a disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, reducing the rate of disease progression, alleviating or temporarily ameliorating the disease state; remission or improving the prognosis. Specifically, the administration of the composition of the present invention includes all actions to improve the degenerative brain disease or its related symptoms.
본 발명의 다른 하나의 양태는 1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아 화합물 또는 이의 식품학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 뇌질환 예방 또는 개선용 식품 조성물을 제공한다. In another embodiment of the present invention, 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea compound or a pharmaceutically acceptable salt thereof is included as an active ingredient It provides a food composition for preventing or improving degenerative brain disease.
상기 1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아 화합물, 퇴행성 뇌질환, 및 예방 등은 다른 양태에서 기재된 바와 같다.The 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea compound, degenerative brain disease, and prevention are the same as those described in other embodiments.
본 발명의 용어, "식품적으로 허용 가능한 염"은 양이온과 음이온이 정전기적 인력에 의해 결합하고 있는 물질인 염 중에서도 식품학적으로 사용될 수 있는 형태의 염을 의미하며, 통상적으로 금속염, 유기염기와의 염, 무기산과의 염, 유기산과의 염, 염기성 또는 산성 아미노산과의 염 등이 될 수 있으나, 식품학적으로 허용된다면 그 종류에 제한되지 않는다.As used herein, the term "food-acceptable salt" refers to a salt in a form that can be used foodologically among salts, which are substances in which cations and anions are combined by electrostatic attraction, and is usually a metal salt, an organic base and salts, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc., but is not limited to the type as long as the food is acceptable.
본 발명의 용어 "식품"은 육류, 소시지, 빵, 초콜릿, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올음료, 비타민 복합체, 건강 기능 식품 및 건강 식품 등이 있으며, 통상적인 의미의 식품을 모두 포함한다.As used herein, the term "food" refers to meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, There are vitamin complexes, health functional foods, and health foods, and includes all foods in the ordinary sense.
상기 건강기능(성) 식품(functional food)이란, 특정보건용 식품(food for special health use, FoSHU)와 동일한 용어로, 영양 공급 외에도 생체조절기능이 효율적으로 나타나도록 가공된 의학, 의료효과가 높은 식품을 의미한다. 여기서 "기능(성)"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 식품은 당 업계에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조 시에는 당 업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 상기 식품의 제형 또한 식품으로 인정되는 제형이면 제한 없이 제조될 수 있다. 본 발명의 식품용 조성물은 다양한 형태의 제형으로 제조될 수 있으며, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나, 본 발명의 식품은 퇴행성 뇌질환 예방 또는 개선 효과를 증진시키기 위한 보조제로 섭취가 가능하다.The functional food (functional food) is the same term as food for special health use (FoSHU), and in addition to supplying nutrients, it is processed to efficiently exhibit bioregulatory functions and has high medical effects. means food. Here, "function (sex)" means to obtain a useful effect for health purposes such as regulating nutrients or physiological action with respect to the structure and function of the human body. The food of the present invention can be prepared by a method commonly used in the art, and at the time of manufacture, it can be prepared by adding raw materials and components commonly added in the art. In addition, the formulation of the food may be prepared without limitation as long as it is a formulation recognized as a food. The composition for food of the present invention can be prepared in various forms, and unlike general drugs, it has the advantage that there are no side effects that may occur during long-term administration of the drug using food as a raw material, and has excellent portability, and the present invention can be consumed as a supplement to enhance the effect of preventing or improving degenerative brain disease.
상기 건강 식품(health food)은 일반식품에 비해 적극적인 건강유지나 증진 효과를 가지는 식품을 의미하고, 건강보조식품(health supplement food)는 건강보조 목적의 식품을 의미한다. 경우에 따라, 건강 기능 식품, 건강식품, 건강보조식품의 용어는 혼용된다.The health food means a food having an active health maintenance or promotion effect compared to general food, and the health supplement food means a food for the purpose of health supplementation. In some cases, the terms health functional food, health food, and dietary supplement are used interchangeably.
구체적으로, 상기 건강 기능 식품은 1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아 화합물 또는 이의 식품학적으로 허용 가능한 염을 음료, 차류, 향신료, 껌, 과자류 등의 식품소재에 첨가하거나, 캡슐화, 분말화, 현탁액 등으로 제조한 식품으로, 이를 섭취할 경우 건강상 특정한 효과를 가져오는 것을 의미하나, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용이 없는 장점이 있다.Specifically, the health functional food is 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea compound or a pharmaceutically acceptable salt thereof in beverages, teas, Foods added to food materials such as spices, gums, and confectionery, or manufactured by encapsulation, powdering, or suspension. This has the advantage that there are no side effects that may occur during long-term use of the drug.
본 발명의 식품 조성물은, 일상적으로 섭취하는 것이 가능하기 때문에 높은 퇴행성 뇌질환 치매 예방 또는 개선 효과를 기대할 수 있어 매우 유용하다.Since the food composition of the present invention can be ingested on a daily basis, it can be expected to have a high effect of preventing or improving dementia due to degenerative brain disease, and is very useful.
상기 조성물은 생리학적으로 허용 가능한 담체를 추가로 포함할 수 있는데, 담체의 종류는 특별히 제한되지 아니하며 당해 기술 분야에서 통상적으로 사용되는 담체라면 어느 것이든 사용할 수 있다.The composition may further include a physiologically acceptable carrier, the type of carrier is not particularly limited, and any carrier commonly used in the art may be used.
또한, 상기 조성물은 식품 조성물에 통상 사용되어 냄새, 맛, 시각 등을 향상시킬 수 있는 추가 성분을 포함할 수 있다. 예들 들어, 비타민 A, C, D, E, B1, B2, B6, B12, 니아신(niacin), 비오틴(biotin), 폴레이트(folate), 판토텐산(panthotenic acid) 등을 포함할 수 있다. 또한, 아연(Zn), 철(Fe), 칼슘(Ca), 크롬(Cr), 마그네슘(Mg), 망간(Mn), 구리(Cu), 크륨(Cr) 등의 미네랄을 포함할 수 있다. 또한, 라이신, 트립토판, 시스테인, 발린 등의 아미노산을 포함할 수 있다. In addition, the composition may include additional ingredients that are commonly used in food compositions to improve odor, taste, vision, and the like. For example, vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, pantothenic acid, and the like may be included. Also, it may include minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu), and chromium (Cr). In addition, it may include amino acids such as lysine, tryptophan, cysteine, and valine.
또한, 상기 식품 조성물은 방부제(소르빈산 칼륨, 벤조산나트륨, 살리실산, 데히드로초산나트륨 등), 살균제(표백분과 고도 표백분, 차아염소산나트륨 등), 산화방지제(부틸히드록시아니졸(BHA), 부틸히드록시톨류엔(BHT) 등), 착색제(타르색소 등), 발색제(아질산 나트륨, 아초산 나트륨 등), 표백제(아황산나트륨), 조미료(MSG 글루타민산나트륨 등), 감미료(둘신, 사이클레메이트, 사카린, 나트륨 등), 향료(바닐린, 락톤류 등), 팽창제(명반, D-주석산수소칼륨 등), 강화제, 유화제, 증점제(호료), 피막제, 검기초제, 거품억제제, 용제, 개량제 등의 식품 첨가물(food additives)을 포함할 수 있다. 상기 첨가물은 식품의 종류에 따라 선별되고 적절한 양으로 사용될 수 있다.In addition, the food composition includes a preservative (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), a disinfectant (bleaching powder and high bleaching powder, sodium hypochlorite, etc.), an antioxidant (butylhydroxyanisole (BHA), butyl hydro Loxytoluene (BHT), etc.), coloring agents (tar pigments, etc.), coloring agents (sodium nitrite, sodium nitrite, etc.), bleach (sodium sulfite), seasonings (MSG sodium glutamate, etc.), sweeteners (dulcin, cyclamate, saccharin, etc.) , sodium, etc.), flavorings (vanillin, lactones, etc.), swelling agents (alum, D-potassium hydrogen tartrate, etc.), strengthening agents, emulsifiers, thickeners (flavors), film agents, gum base agents, foam inhibitors, solvents, improvers, etc. It may contain food additives. The additive may be selected according to the type of food and used in an appropriate amount.
상기 화합물 또는 이의 식품학적으로 허용 가능한 염을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 그의 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 일반적으로, 식품 또는 음료의 제조 시에 본 발명의 식품 조성물은 식품 또는 음료에 대하여 50 중량부 이하, 구체적으로 20 중량부 이하의 양으로 첨가될 수 있다. 그러나 건강 및 위생을 목적으로 장기간 섭취할 경우에는 상기 범위 이하의 함량을 포함할 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.The compound or a pharmaceutically acceptable salt thereof may be added as it is, or it may be used together with other foods or food ingredients, and may be appropriately used according to a conventional method. The mixed amount of the active ingredient may be suitably determined according to the purpose of its use (prevention, health or therapeutic treatment). In general, in the production of food or beverage, the food composition of the present invention may be added in an amount of 50 parts by weight or less, specifically 20 parts by weight or less with respect to the food or beverage. However, when ingested for a long period of time for health and hygiene purposes, it may contain an amount below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
본 발명의 식품 조성물의 일 예로 건강음료 조성물로 사용될 수 있으며, 이 경우 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로 함유할 수 있다. 상술한 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드; 말토스, 슈크로스와 같은 디사카라이드; 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드; 자일리톨, 소르비톨, 에리트리톨 등의 당알콜일 수 있다. 감미제는 타우마틴, 스테비아 추출물과 같은 천연 감미제; 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 mL 당 일반적으로 약 0.01 ~ 0.04 g, 구체적으로는 약 0.02 ~ 0.03 g 일 수 있다.As an example of the food composition of the present invention, it may be used as a health drink composition, and in this case, it may contain various flavoring agents or natural carbohydrates as an additional component like a conventional drink. The above-mentioned natural carbohydrates include monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; polysaccharides such as dextrin and cyclodextrin; It may be a sugar alcohol such as xylitol, sorbitol, or erythritol. Sweeteners include natural sweeteners such as taumatine, stevia extract; A synthetic sweetener such as saccharin or aspartame may be used. The proportion of the natural carbohydrate may be generally about 0.01 to 0.04 g, specifically, about 0.02 to 0.03 g per 100 mL of the composition of the present invention.
상기 외에 건강음료 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산, 펙트산의 염, 알긴산, 알긴산의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올 또는 탄산화제 등을 함유할 수 있다. 그 밖에 천연 과일주스, 과일주스 음료, 또는 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 혼합하여 사용할 수 있다. 이러한 첨가제의 비율은 크게 중요하진 않지만 본 발명의 조성물 100 중량부당 0.01 ~ 0.1 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above, the health beverage composition includes various nutrients, vitamins, electrolytes, flavoring agents, colorants, pectic acid, pectic acid salts, alginic acid, alginic acid salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, It may contain alcohol, a carbonation agent, and the like. In addition, it may contain the pulp for the production of natural fruit juice, fruit juice beverage, or vegetable beverage. These components may be used independently or in combination. The proportion of these additives is not very important, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.
본 발명의 식품 조성물은 퇴행성 뇌질환 예방 또는 개선 효과를 나타낼 수 있다면 다양한 중량%로 포함할 수 있으나, 구체적으로 1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아 또는 이의 식품학적으로 허용 가능한 염을 식품 조성물의 총중량 대비 0.00001 내지 100 중량% 또는 0.01 내지 80 중량%로 포함할 수 있다.The food composition of the present invention may contain various weight % as long as it can exhibit the effect of preventing or improving degenerative brain disease, but specifically 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridine -3-Nyl}urea or a pharmaceutically acceptable salt thereof may be included in an amount of 0.00001 to 100% by weight or 0.01 to 80% by weight relative to the total weight of the food composition.
본 발명에서 "개선"은 본 발명의 식품, 의약외품, 또는 사료 조성물의 투여로 퇴행성 뇌질환이 호전 또는 이롭게 변경되는 모든 행위를 의미한다.In the present invention, "improvement" refers to any action in which the degenerative brain disease is improved or changed advantageously by the administration of the food, quasi-drug, or feed composition of the present invention.
본 발명의 또 다른 하나의 양태는 1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아 화합물 또는 이의 의약외품학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 뇌질환 예방 또는 개선용 의약외품 조성물을 제공한다.In another embodiment of the present invention, 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea compound or a quasi-pharmaceutically acceptable salt thereof is used as an active ingredient. It provides a quasi-drug composition for preventing or improving degenerative brain disease, including.
상기 1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아 화합물, 퇴행성 뇌질환, 예방, 및 개선 등은 다른 양태에서 기재된 바와 같다.The 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea compound, degenerative brain disease, prevention, improvement, and the like are the same as described in other embodiments.
본 발명의 용어, "의약외품학적으로 허용 가능한 염"은 양이온과 음이온이 정전기적 인력에 의해 결합하고 있는 물질인 염 중에서도 의약외품학적으로 사용될 수 있는 형태의 염을 의미하며, 통상적으로 금속염, 유기염기와의 염, 무기산과의 염, 유기산과의 염, 염기성 또는 산성 아미노산과의 염 등이 될 수 있으나, 의약외품적으로 허용된다면 그 종류에 제한되지 않는다.As used herein, the term "quasi-drugally acceptable salt" refers to a salt in a form that can be used quasi-drugally among salts in which cations and anions are combined by electrostatic attraction, and are usually used with metal salts, organic bases and salts, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc., but are not limited thereto as long as they are permitted quasi-drugs.
본 발명에서 용어 "의약외품"은 의약외품에 해당되는 내복용 제제, 저함량 비타민, 미네랄 제제, 소독 청결제, 세정제, 및 연고제로 이루어진 군에서 선택되는 것일 수 있으나, 이에 제한되지 않는다.In the present invention, the term "quasi-drug" may be selected from the group consisting of oral preparations, low-content vitamins, mineral preparations, disinfectants, detergents, and ointments corresponding to quasi-drugs, but is not limited thereto.
본 발명의 의약외품 조성물에는 상기 성분 외에 필요에 따라 의약외품학적으로 허용 가능한 담체, 부형제 또는 희석제를 더욱 포함할 수 있다. 상기 허용 가능한 담체, 부형제 또는 희석제는 본 발명의 효과를 해하지 않는 한 제한되지 않으며, 예를 들어 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제, 윤활제, 감미제, 방향제, 보존제 등을 포함할 수 있다.The quasi-drug composition of the present invention may further include a quasi-pharmaceutically acceptable carrier, excipient or diluent, if necessary, in addition to the above components. The acceptable carrier, excipient or diluent is not limited as long as it does not impair the effects of the present invention, and may include, for example, fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, sweeteners, fragrances, preservatives, and the like. have.
본 발명의 의약외품학적으로 허용 가능한 담체, 부형제 또는 희석제의 대표적인 예로는, 락토즈, 덱스트로스, 슈크로스, 솔비톨, 만니톨, 자일리톨, 말티톨, 전분, 젤라틴, 글리세린, 아카시아 고무, 알지네이트, 칼슘포스페이트, 칼슘카보네이트, 칼슘실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트, 광물유, 프로필렌글리콜, 폴리에틸렌글리콜, 식물성 오일, 주사가능한 에스테르, 위텝솔, 마크로골, 트윈 61, 카카오지, 라우리지 등을 들 수 있다.Representative examples of the quasi-pharmaceutically acceptable carrier, excipient or diluent of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, maltitol, starch, gelatin, glycerin, acacia gum, alginate, calcium phosphate, calcium Carbonate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, propylene glycol, polyethylene glycol, vegetable oil , injectable esters, Witepsol, Macrogol, Tween 61, cacao butter, laurage, and the like.
본 발명의 화합물 또는 이의 의약외품학적으로 허용 가능한 염을 의약외품의 유효성분으로 사용하는 경우, 추가로 동일 또는 유사한 기능을 나타내는 유효성분을 1종 이상 함유할 수 있다. 상기 성분 추가 시에는 복합 사용에 따른 안전성, 제형화의 용이성, 유효성분들의 안정성을 고려할 수 있다.When the compound of the present invention or a quasi-pharmaceutically acceptable salt thereof is used as an active ingredient of a quasi-drug, it may further contain one or more active ingredients exhibiting the same or similar function. When adding the above ingredients, safety according to combined use, ease of formulation, and stability of active ingredients can be considered.
의약외품의 제제화 방법, 용량, 이용방법, 구성성분 등은 기술분야에 공지된 통상의 기술로부터 적절히 선택될 수 있다.The formulation method, dose, usage method, component, etc. of the quasi-drug may be appropriately selected from conventional techniques known in the art.
본 발명의 또 다른 하나의 양태는 1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아 화합물 또는 이의 사료학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 뇌질환 예방 또는 개선용 사료 조성물을 제공한다.Another aspect of the present invention is a 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea compound or a phytochemically acceptable salt thereof as an active ingredient. It provides a feed composition for preventing or improving degenerative brain disease, including.
상기 1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아 화합물, 퇴행성 뇌질환, 예방, 및 개선 등은 다른 양태에서 기재된 바와 같다.The 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea compound, degenerative brain disease, prevention, improvement, and the like are the same as described in other embodiments.
본 발명의 용어, "사료학적으로 허용 가능한 염"은 양이온과 음이온이 정전기적 인력에 의해 결합하고 있는 물질인 염 중에서도 사료학적으로 사용될 수 있는 형태의 염을 의미하며, 통상적으로 금속염, 유기염기와의 염, 무기산과의 염, 유기산과의 염, 염기성 또는 산성 아미노산과의 염 등이 될 수 있으나, 사료적으로 허용된다면 그 종류에 제한되지 않는다.As used herein, the term "forage acceptable salt" refers to a salt in a form that can be used for fodder among salts in which cations and anions are combined by electrostatic attraction, usually with metal salts, organic bases and salts, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc., but is not limited to the type as long as it is acceptable for feed.
상기 사료 조성물에는 상기 화합물 또는 이의 사료학적으로 허용 가능한 염 외에도 약학적, 식품학적 또는 사료용으로 허용되는 공지의 담체, 안정화제, 또는 첨가제가 포함될 수 있다. 예를 들어, 품질 저하를 방지하기 위하여 첨가하는 결착제, 유화제, 보존제 등이 있고, 효용 증대를 위하여 사료에 첨가하는 아미노산제, 비타민제, 효소제, 향미제, 비단백질태질소화합물, 규산염제, 완충제, 추출제, 올리고당 등이 있다. 그 외에도 사료 혼합제 등을 추가로 포함할 수 있으며 이에 한정된 것은 아니다. 상기 사료 조성물은 필요에 따라 비타민, 아미노산류, 미네랄 등의 각종 양분, 항산화제 및 기타의 첨가제 등을 포함할 수도 있으며, 그 형상으로서는 분체, 과립, 펠릿, 현탁액 등의 적당한 상태일 수 있다. 본 발명의 사료 조성물은 단위 동물에 대하여 단독으로 또는 사료에 혼합하여 공급할 수 있다. 본 발명의 사료는 특별히 한정되는 것은 아니고, 분말 사료, 고형 사료, 건사료, 습식사료, 모이스트 펠릿 사료, 드라이 펠릿 사료, EP(Extruder Pellet) 사료, 날먹이 등 어떠한 사료라도 무방하다.The feed composition may include a known carrier, stabilizer, or additive that is acceptable for pharmaceutical, food, or feed in addition to the compound or a pharmaceutically acceptable salt thereof. For example, there are binders, emulsifiers, preservatives, etc. added to prevent quality deterioration, and amino acids, vitamins, enzymes, flavoring agents, non-protein nitrogen compounds, silicate agents, buffers added to feed to increase efficacy , extractants, and oligosaccharides. In addition, it may further include a feed mixture, and the like, but is not limited thereto. The feed composition may contain various nutrients such as vitamins, amino acids, minerals, antioxidants, and other additives as necessary, and may be in a suitable state such as powder, granule, pellet, suspension, etc. The feed composition of the present invention may be supplied alone or mixed with feed for a unit animal. The feed of the present invention is not particularly limited, and any feed such as powder feed, solid feed, dry feed, wet feed, moist pellet feed, dry pellet feed, EP (Extruder Pellet) feed, raw feed, etc. may be used.
본 발명의 또 다른 하나의 양태는 본 발명의 식품, 의약외품, 또는 사료 조성물을 개체에 투여하는 단계를 포함하는 퇴행성 뇌질환 예방 또는 치료 방법을 제공한다.Another aspect of the present invention provides a method for preventing or treating degenerative brain disease comprising administering the food, quasi-drug, or feed composition of the present invention to an individual.
상기 식품 조성물, 의약외품 조성물, 사료 조성물, 개체, 투여, 퇴행성 뇌질환, 예방, 및 개선 등은 다른 양태에서 기재된 바와 같다.The food composition, quasi-drug composition, feed composition, individual, administration, degenerative brain disease, prevention, and improvement are the same as described in other embodiments.
본 발명에서 후성유전학과 관련된 MeCP2를 저해하는 신규한 화합물을 확인하였으며, 상기 화합물은 기존의 치료제보다 효과적인 퇴행성 뇌질환 치료제로 적용될 수 있다. In the present invention, a novel compound that inhibits MeCP2 related to epigenetics has been identified, and the compound can be applied as a therapeutic agent for degenerative brain disease that is more effective than existing therapeutic agents.
도 1은 ensECBS 방법의 모식도를 나타낸 도이다.
도 2는 stable cell line을 구축에 대한 모식도를 나타낸 도이다.
도 3은 stable cell line에서 MeCP2 mRNA 수준을 나타낸 도이다.
도 4는 stable cell line에서 MeCP2 단백질 수준을 나타낸 도이다.
도 5는 신규한 MeCP2 저해제 화합물이 MeCP2를 감소시킴을 나타낸 도이다.
도 6은 동물실험 모식도를 나타낸 도이다.
도 7은 Y-maze 테스트 결과를 나타낸 도이다.
도 8은 새로운 사물 인지 실험(Novel object recognition test) 결과를 나타낸 도이다.
도 9는 수동회피실험 결과를 나타낸 도이다.
도 10은 열린 공간 실험 결과 중 거리 데이터를 나타낸 도이다.
도 11은 열린 공간 실험 결과 중 중간 체류시간 데이터를 나타낸 도이다.
도 12는 로타로드 실험 결과를 나타낸 도이다.
도 13 및 도 14는 3 챔버 테스트 결과를 나타낸 도이다.
도 15는 아밀로이드 B 플라그(amyloid B plaque) 발현 수준의 측정 결과를 나타낸 도이다.
도 16은 배측 해마 (dorsal hippocampus)에서 MeCP2, NeuN, DAPI에 대한 ICH 분석 결과를 나타낸 도이다.
도 17은 후각 피질(Entorhinal cortex)에서 MeCP2, NeuN, DAPI에 대한 ICH 분석 결과를 나타낸 도이다.
도 18은 복측 선조체(Ventral striatum)에서 MeCP2, NeuN, DAPI에 대한 ICH 분석 결과를 나타낸 도이다.
도 19는 복측 해마 (Ventral hippocampus)에서 MeCP2, NeuN, DAPI에 대한 ICH 분석 결과를 나타낸 도이다.1 is a diagram showing a schematic diagram of the ensECBS method.
2 is a diagram showing a schematic diagram for constructing a stable cell line.
3 is a diagram showing MeCP2 mRNA levels in stable cell lines.
4 is a diagram showing the level of MeCP2 protein in a stable cell line.
5 is a diagram showing that a novel MeCP2 inhibitor compound reduces MeCP2.
6 is a diagram showing a schematic diagram of an animal experiment.
7 is a diagram showing the results of the Y-maze test.
8 is a diagram illustrating a result of a novel object recognition test.
9 is a diagram showing the results of the passive avoidance experiment.
10 is a diagram illustrating distance data among the results of an open space experiment.
11 is a diagram showing intermediate residence time data among the results of an open space experiment.
12 is a view showing the results of the rotarod experiment.
13 and 14 are diagrams illustrating a three-chamber test result.
15 is a view showing the measurement result of amyloid B plaque (amyloid B plaque) expression level.
16 is a diagram showing the results of ICH analysis for MeCP2, NeuN, and DAPI in the dorsal hippocampus.
17 is a diagram showing the results of ICH analysis for MeCP2, NeuN, and DAPI in the entorhinal cortex.
18 is a diagram showing the ICH analysis results for MeCP2, NeuN, DAPI in the ventral striatum (Ventral striatum).
19 is a diagram showing the ICH analysis results for MeCP2, NeuN, DAPI in the ventral hippocampus.
이하 본 발명을 실시예를 통하여 보다 상세하게 설명한다. 그러나 이들 실시예 및 실험예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예 및 실험예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples. However, these Examples and Experimental Examples are for illustrative purposes of the present invention, and the scope of the present invention is not limited to these Examples and Experimental Examples.
실시예 1: ensECBS를 이용한 신규한 MeCP2 저해제 화합물 발굴Example 1: discovery of novel MeCP2 inhibitor compounds using ensECBS
기존의 퇴행성 뇌질환 치료제 연구에서 한걸음 더 나아가 후성유전학적 기전과 관련된 MeCP2를 저해하는 화합물을 이용한 치료제를 발굴하고자 하였다. 구체적으로, 기존의 치료제와는 달리, 퇴행성 뇌질환, 특히 알츠하이머성 치매 발병 및 진행과 관련된 후성유전학과 관련이 있는 MeCP2(Methyl-CpG-binding protein 2)를 저해하는 신규한 물질을 발굴하고자 하였다.An attempt was made to discover a therapeutic agent using a compound that inhibits MeCP2, which is related to an epigenetic mechanism, going one step further from the existing research on the treatment of degenerative brain disease. Specifically, unlike existing therapeutics, it was attempted to discover a novel substance that inhibits MeCP2 (Methyl-CpG-binding protein 2), which is related to epigenetics related to the onset and progression of degenerative brain disease, particularly Alzheimer's dementia.
구체적으로, 인공지능(Artificial Intelligence: AI) 딥러닝 기술(ensECBS)을 이용한 스크리닝 방법을 통해 신규한 MeCP2 저해제를 발굴하였다. 이러한 방법의 모식도는 도 1에 나타내었다.Specifically, a novel MeCP2 inhibitor was discovered through a screening method using artificial intelligence (AI) deep learning technology (ensECBS). A schematic diagram of this method is shown in FIG. 1 .
기존의 MeCP2를 저해한다고 알려진 6종의 화합물(US 9034574 B2)을 학습시킨 후 서로 다른 특징을 갖는 화합물 결합 유사성 (chemical binding similarity) 예측 모델(ensECBS)을 이용하여 화합물을 확인하였다. ensECBS 모델은 지정된 타겟 없이 일반적인 화합물 결합 유사성을 계산하는 특징을 가진다. 상기 모델을 이용하여 MeCP2에 결합하는 화합물을 발굴하였으며, MeCP2 저해제 후보 화합물을 화합물 데이터베이스로부터 선별하였다.After training six types of compounds known to inhibit MeCP2 (US 9034574 B2), the compounds were identified using a chemical binding similarity prediction model (ensECBS) with different characteristics. The ensECBS model is characterized by calculating general compound binding similarity without a specified target. Compounds binding to MeCP2 were discovered using the above model, and MeCP2 inhibitor candidate compounds were selected from the compound database.
실시예 2: 발굴한 화합물의 MeCP2 저해 확인Example 2: Confirmation of MeCP2 Inhibition of Discovered Compounds
MeCP2의 C-말단에서 EGFP를 발현하는 stable cell line을 구축하였고, 이를 대상으로 화합물의 MeCP2 저해 여부를 확인하였다. 이를 위하여, MeCP2에 EGFP (녹색 형광) 가 부착된 단백질과 Dsred (붉은 형광) 벡터를 HEK293 (신장세포) 에 transduction하여, MeCP2-EGFP를 지속적으로 발현하는 stable cell line을 구축하였다 (도 2).A stable cell line expressing EGFP at the C-terminus of MeCP2 was constructed, and it was confirmed whether the compound inhibited MeCP2. To this end, a stable cell line continuously expressing MeCP2-EGFP was constructed by transduction of a protein with EGFP (green fluorescence) attached to MeCP2 and a Dsred (red fluorescence) vector into HEK293 (kidney cells) ( FIG. 2 ).
이후, MeCP2 stable cell line (Mecp2 C-말단에 EGFP가 부착된 단백질과 DsRed를 독립적으로 발현하는 stable cell line) 이 적절하게 구축되었는지 확인하기 위해, stable cell line에서 MeCP2 mRNA 수준의 증가를 qRT-PCR을 통해 확인하였고(도 3), stable cell line에서 MeCP2 단백질 수준의 증가를 웨스턴 블럿을 통해 확인하였다(도 4).Thereafter, in order to confirm that a MeCP2 stable cell line (a stable cell line expressing Mecp2 C-terminally EGFP-attached protein and DsRed independently) was properly constructed, the increase in MeCP2 mRNA level in the stable cell line was measured by qRT-PCR. was confirmed through (FIG. 3), and the increase in MeCP2 protein level in stable cell lines was confirmed by Western blot (FIG. 4).
qRT-PCR은 역전사를 통해 cDNA를 제조하기 위해, control stable cell line과 MeCP2 stable cell line에서 세포를 채취한 후, 이로부터 총 50ng의 RNA를 분리하였다. mRNA의 경우 제조업체의 프로토콜에 따라 ReverseTra Ace qPCR RT Mix (TOYOBO)를 사용하여 cDNA를 증폭시켰다. 다음으로, iQ SYBR Green Supermix(Bio-Rad)에 MeCP2 와 GAPDH primer를 섞어준 후 quantitative real-time PCR (qRT-PCR)을 사용하여 mRNA의 발현을 정량화하였다. 상기 qRT-PCR 반응은 CFX connect(Bio-Rad)에서 수행하였다. 상기 결과로부터 측정된 miRNA와 mRNA의 상대비 (relative abundance)는 2-ddCt 방법으로 확인하였다. GAPDH는 stable cell line에 있는 MeCP2 정량화를 위한 표준화 대조군으로 사용하였다. In qRT-PCR, to prepare cDNA through reverse transcription, cells were collected from a control stable cell line and a MeCP2 stable cell line, and a total of 50 ng of RNA was isolated therefrom. For mRNA, cDNA was amplified using ReverseTra Ace qPCR RT Mix (TOYOBO) according to the manufacturer's protocol. Next, mRNA expression was quantified using quantitative real-time PCR (qRT-PCR) after mixing MeCP2 and GAPDH primers in iQ SYBR Green Supermix (Bio-Rad). The qRT-PCR reaction was performed in CFX connect (Bio-Rad). The relative abundance of miRNA and mRNA measured from the above results was confirmed by the 2 -ddCt method. GAPDH was used as a standardized control for MeCP2 quantification in stable cell lines.
Western blot 은, Control stable cell line과 MeCP2 stable cell line로부터 RIPA 완충용액(Thermo Fisher Scientific)을 사용하여 단백질을 추출하였다. 이때, 추출과정은 제조사 프로토콜에 따라 진행하였다. 추출한 단백질 시료에서 단백질의 농도는 Pierce BCA protein assay (Thermo Fisher Scientific)와 분광광도계(spectrophotometer)를 통해 정량화하였다. 우선 상기 단백질 (75ug/lane) 시료를 SDS-PAGE에 로딩하고, PVDF막으로 옮겼다. 상기 PVDF 막을 5% BSA (Bovine Serum Albumin)로 1시간 동안 처리한 후, 세척하였다. 여기에 4도에서 일차 항체를 처리하고, 밤새(overnight) 반응시킨 다음 상온에서 2시간 배양하였다. 이때 사용한 일차 항체는 다음과 같다. : rabbit anti-MeCP2(Millipore; 1:750), mouse anti-b actin(Santa Cruz; 1:2000). 이어서, 일차 항체가 결합된 막을 세척하고 Goat anti-Rabbit IgG-HRP (Abcam; 1:2000) 또는 Goat anti-mouse IgG-HRP(Invitrogen; 1:5000)를 상온에서 2시간도안 배양하였다. HRP 신호는 SuperSignal West Pico Chemiluminescent Substrate (Thermo Fisher Scientific)과 Image Quant LAS4000(GE Healthcare Bio-science)를 사용하여 가시화 하였다. 정량적 밀도 측정 비교 (Quantitative densitometric comparison)를 위해, Image J를 사용하였다. 본 실험에서, 동일한 시료에 대한 블롯으로부터 시료를 대응되게 처리하고, 로딩 대조군(B-actin)은 타겟 (MeCP2)로써 동일한 플롯에서 수행하였다. For Western blot, proteins were extracted from Control stable cell lines and MeCP2 stable cell lines using RIPA buffer (Thermo Fisher Scientific). At this time, the extraction process was performed according to the manufacturer's protocol. The protein concentration in the extracted protein sample was quantified using a Pierce BCA protein assay (Thermo Fisher Scientific) and a spectrophotometer. First, the protein (75ug/lane) sample was loaded on SDS-PAGE and transferred to a PVDF membrane. The PVDF membrane was treated with 5% BSA (Bovine Serum Albumin) for 1 hour, and then washed. Here, the primary antibody was treated at 4 degrees, reacted overnight, and then incubated for 2 hours at room temperature. The primary antibodies used at this time are as follows. : rabbit anti-MeCP2 (Millipore; 1:750), mouse anti-b actin (Santa Cruz; 1:2000). Then, the membrane to which the primary antibody was bound was washed, and Goat anti-Rabbit IgG-HRP (Abcam; 1:2000) or Goat anti-mouse IgG-HRP (Invitrogen; 1:5000) was incubated at room temperature for 2 hours. HRP signals were visualized using SuperSignal West Pico Chemiluminescent Substrate (Thermo Fisher Scientific) and Image Quant LAS4000 (GE Healthcare Bio-science). For quantitative densitometric comparison, Image J was used. In this experiment, samples from the blots for the same sample were treated correspondingly, and the loading control (B-actin) was performed on the same plot as the target (MeCP2).
그 결과, 도 3 및 도 4에 나타난 바와 같이, stable cell line에 MeCP2-EGFP가 안정적으로 발현되고 있음을 확인하였다.As a result, as shown in FIGS. 3 and 4 , it was confirmed that MeCP2-EGFP was stably expressed in stable cell lines.
또한, 화합물의 MeCP2 저해를 확인하기 위해, 용해된 화합물을 0.1nM, 1nM, 10nM, 100nM, 1uM, 10uM, 및 100uM 농도로 culture media(DMEM + FBS 10%)에 혼합한 후, MeCP2의 C-말단에서 EGFP를 발현하고, DsRed를 독립적으로 발현하는 하는 stable cell line에 분주하였다. 대조군(DMSO)과 실험군(화합물+DMSO)에서 DMSO의 함량은 전체 배양 배지(culture media)에서 1%가 되도록 하여 실험을 진행하였다. 배양 배지가 제거된 상태에서 분광광도계(spectrophotometer)를 사용하여 EGFP는 Exc/Emi = 488/509에서 측정하였고, DsRed는 Exc/Emi = 558/583에서 측정하였다. DsRed는 stable cell line에 존재하는 MeCP2-EGFP 정량화를 위한 표준화 대조군으로서 사용하였다. 측정한 MeCP2-EGFP(green)와 DsRed(red) 강도를 비교하여 표준화하였다. In addition, in order to confirm the MeCP2 inhibition of the compound, the dissolved compound was mixed in culture media (DMEM +
그 결과, 도 5에 나타난 바와 같이, 1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아는 MeCP2를 가장 효과적으로 감소시켰고 IC50은 14.97nM을 나타내었다.As a result, as shown in FIG. 5, 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea reduced MeCP2 most effectively and IC 50 was 14.97 nM. was shown.
실시예 3: 1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아의 퇴행성 뇌질환 치료 효과 확인Example 3: Confirmation of the therapeutic effect of 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea for degenerative brain disease
실시예 3-1: 실험 개요Example 3-1: Experimental Overview
1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아를 실제 알츠하이머병 질병 마우스(APP/PS1)에 복강내 주사(Intraperitoneal injection; IP injection)하고 행동실험 후 MeCP2, NeuN, 및 amyloid B plaque의 발현 수준을 측정하였다.Intraperitoneal injection (IP injection) of 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea into real Alzheimer's disease disease mice (APP/PS1) After the behavioral experiments, the expression levels of MeCP2, NeuN, and amyloid B plaques were measured.
1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아를 PEG400, Saline, 및 DMSO를 40 : 57 : 3 비율로 만든 용액에 녹였다. 이의 전체적인 투여(IP 주사) 방식은 도 6에 나타내었으며, 구체적으로, 투여는 하루에 한 번씩 15mg/Kg로 4 주 동안 수행하였고 알츠하이머 마우스 (APP/PS1)의 인지저하가 일어난다고 알려진 9개월 이전으로서, 8개월령부터 실험을 수행하였다. 각각의 투여 시료에 따라 WT-vehicle, WT-chemical, APP/PS1-vehicle, 및 APP/PS1-chemical 와 같은 4개의 군으로 다음과 같이 구분하였다. 이 때, chemical은 1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아를 의미한다.1-Phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea was dissolved in a solution made of PEG400, Saline, and DMSO in a 40:57:3 ratio. Its overall administration (IP injection) mode is shown in FIG. 6 , and specifically, administration was performed once a day at 15 mg/Kg for 4 weeks and before 9 months of known cognitive decline in Alzheimer's mice (APP/PS1). As such, the experiment was performed from the age of 8 months. According to each administration sample, it was divided into 4 groups such as WT-vehicle, WT-chemical, APP/PS1-vehicle, and APP/PS1-chemical as follows. In this case, chemical means 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea.
복강 내 주입 후 마우스의 인지 기능을 확인을 위한 행동실험으로, Y-maze 테스트, 새로운 사물 인지 실험(Novel object recognition test; NOR), 및 수동회피실험(passive avoidance; PA); 사회성을 확인하기 위한 three chamber test(3CT); 운동능(locomotor) 및 불안 수준(anxiety level)를 확인하기 위한 열린 공간 실험(Open field test; OF); 및 운동 능력을 확인하기 위한 로타로드 실험(rotarod test; Rotarod)를 진행하였다. 상기 Y-maze, NOR, PA, 3CT, OF, 및 Rotarod 실험 모두 공지된 방법을 이용하였다.Behavioral experiments for confirming the cognitive function of mice after intraperitoneal injection, Y-maze test, novel object recognition test (NOR), and passive avoidance (PA); three chamber test (3CT) to confirm sociality; Open field test (OF) to check locomotor and anxiety level; And rotarod test (Rotarod test; Rotarod) to confirm the exercise was performed. The Y-maze, NOR, PA, 3CT, OF, and Rotarod experiments all used a known method.
또한, MeCP2, NeuN, 및 amyloid plaque의 발현 수준을 측정하기 위해 마우스 뇌에서 면역조직화학 (immunohistochemistry; IHC) 분석 및 Thioflavin S 염색을 진행하였다. In addition, to measure the expression levels of MeCP2, NeuN, and amyloid plaques, immunohistochemistry (IHC) analysis and Thioflavin S staining were performed in the mouse brain.
실시예 3-2. 인지기능 개선 확인(Y-maze, NOR, 및 PA)Example 3-2. Identification of cognitive improvement (Y-maze, NOR, and PA)
Y-maze 테스트는 마우스가 Y자 모양 미로에서 앞서 들어갔던 통로를 기억하고 3개의 통로를 순차적으로 돌아다닌다는 습성을 이용한 것으로서, 상기 표 1와 같이 제작한 마우스를 Y자 미로에 놓고 순차적으로 통로를 돌아다닌 정도를 확인하여 인지능력을 측정하였다.The Y-maze test uses the habit that the mouse remembers the passage it entered earlier in the Y-shaped maze and walks around the three passages sequentially. Cognitive ability was measured by checking the degree of walking around.
그 결과, 도 7에 나타난 바와 같이, 알츠하이머 마우스(APP/PS1- vehicle) 그룹에서 순차적으로 통로를 돌아다닌 정도가 감소하였던 반면, chemical을 투여한 알츠하이머 마우스(APP/PS1-chemical) 그룹에서는 정상군(WT-vehicle 및 WT-chemical)에서와 유사하게 그 정도가 증가함을 확인하였다.As a result, as shown in FIG. 7 , the degree of sequentially traversing the passageway was decreased in the Alzheimer's mouse (APP/PS1-vehicle) group, whereas in the chemical-administered Alzheimer's mouse (APP/PS1-chemical) group, the normal group (WT-vehicle and WT-chemical) It was confirmed that the degree increased similarly.
새로운 사물 인지 실험(NOR)은 마우스가 새로운 물체에 더 많은 관심을 보이는 습성을 이용한 것으로서, 상기 표 1와 같이 제작한 마우스에 물체를 먼저 보여주고, 24시간 후에 미리 봤던 물체(familiar object) 및 새로운 물체(novel object)를 동시에 보여줬을 때 어떤 물체에 더 관심을 많이 갖는지 확인하여 인지 능력을 측정하였다.The new object recognition experiment (NOR) uses the habit of the mouse to show more interest in a new object, and shows the object to the mouse prepared as in Table 1 above, and 24 hours later, the previously viewed object (familiar object) and the new object Cognitive ability was measured by checking which object was more interested in when a novel object was shown at the same time.
그 결과, 도 8에 나타난 바와 같이, 알츠하이머 마우스(APP/PS1- chemical) 그룹에서는 새로운 물체에 대한 선호도가 낮았던 반면, chemical을 투여한 알츠하이머 마우스(APP/PS1-chemical) 그룹에서는 정상군(WT-vehicle 및 WT-chemical)에서와 유사하게 그 정도가 증가함을 확인하였다.As a result, as shown in FIG. 8, the Alzheimer's mouse (APP/PS1-chemical) group had a low preference for a new object, whereas the chemical-administered Alzheimer's mouse (APP/PS1-chemical) group had a normal group (WT-) vehicle and WT-chemical), it was confirmed that the degree increased similarly.
수동회피실험은 어두운 방과 밝은 방으로 나뉜 회피학습 상자를 이용하였다. 상자의 밝은 방에 마우스를 넣으면 어두운 방으로 넘어가는데 그 순간 2 초간 0.45 mA의 전기충격을 가하고 다음 날 실험동물을 밝은 방에 다시 넣었을 때 어두운 방에서의 전기충격을 기억하여 밝은 방에 머무르게 되는데, 이때 체류하는 시간(entry latency)을 측정하여 기억력을 평가하였다. The passive avoidance experiment used an avoidance learning box divided into a dark room and a light room. If you put the mouse in the bright room of the box, it goes to the dark room, and at that moment, an electric shock of 0.45 mA is applied for 2 seconds. At this time, the memory was evaluated by measuring the entry latency.
그 결과, 도 9에 나타난 바와 같이, 알츠하이머 마우스(APP/PS1- chemical) 그룹에서는 새로운 물체에 대한 체류시간이 낮았던 반면, chemical을 투여한 알츠하이머 마우스(APP/PS1-chemical) 그룹에서는 정상군(WT-vehicle 및 WT-chemical)에서와 유사하게 그 정도가 증가함을 확인하였다.As a result, as shown in FIG. 9 , the residence time for a new object was low in the Alzheimer's mouse (APP/PS1-chemical) group, whereas in the Alzheimer's mouse (APP/PS1-chemical) group to which the chemical was administered, the normal group (WT) -vehicle and WT-chemical), it was confirmed that the degree increased similarly.
상기 결과를 통해, 인지 저하를 보는 행동실험인 Y-maze, NOR, 및 Passive avoidance 실험 결과 Vehicle을 투여한 알츠하이머 마우스인 APP/PS1-vehicle 그룹이 다른 그룹에 비해 유의미한 인지저하가 나타났다. 그러나, chemical을 투여한 알츠하이머 마우스인 APP/PS1-chemical 그룹은 APP/PS1 vehicle 그룹에 비해 인지 기능이 향상되었다. WT-vehicle, WT-chemical, 및 APP/PS1-chemical group 간의 유의적인 차이는 없었다. Through the above results, as a result of the Y-maze, NOR, and passive avoidance experiments, which are behavioral tests for cognitive decline, the APP/PS1-vehicle group, which is an Alzheimer's mouse administered with a vehicle, showed significant cognitive decline compared to other groups. However, the cognitive function was improved in the APP/PS1-chemical group, which is an Alzheimer's mouse to which the chemical was administered, compared to the APP/PS1 vehicle group. There was no significant difference between the WT-vehicle, WT-chemical, and APP/PS1-chemical groups.
따라서, 1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아가 알츠하이머 마우스의 인지 기능을 향상시킴을 확인하였다.Therefore, it was confirmed that 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea improves cognitive function in Alzheimer's mice.
또한, 모든 자료는 mean(S.E.M)으로 표시하였고, 실험 군 간의 차이는 two-way ANOVA를 이용하여 확인하였다. p>0.05인 경우는 통계적으로 차이가 있다고 판정하였다. p>0.05 ;*, P>0.01 ; **.p>0.001 ; ***In addition, all data were expressed as mean (S.E.M), and the difference between test groups was confirmed using two-way ANOVA. In the case of p>0.05, it was determined that there was a statistical difference. p>0.05 ;*, P>0.01 ; **.p>0.001 ; ***
실시예 3-3. 운동 및 불안 수준 확인(OPM, Rotarod)Example 3-3. Check motor and anxiety levels (OPM, Rotarod)
마우스의 자발적인 보행성 활동량을 측정하고, 불안 수준을 비교하기 위해 열린 공간 테스트(Open field test; OPM)를 수행하였다. 본 실험에 사용된 open field 박스는 가로 40 cm, 세로 40 cm, 높이 40 cm이며, 영상 추적 프로그램(Noldus EthoVision XT)을 사용하여 총 이동 거리 및 가운데 구간에 체류한 시간을 계산하였다. 마우스가 새로운 환경에 적응할 수 있는 시간을 준 이후에, 각 마우스를 같은 코너에 올려두고 행동 관찰을 시작하여 움직이는 경로를 추적하였다. 마우스가 실험 외적인 요인에 의해 원치 않는 어는 행동(freezing behavior)을 보이는 것을 방지하기 위해 조용하고 어두운 방에서 본 실험을 진행하였다. An open field test (OPM) was performed to measure the amount of voluntary ambulatory activity of mice and to compare anxiety levels. The open field box used in this experiment has a width of 40 cm, a length of 40 cm, and a height of 40 cm, and the total distance traveled and the time spent in the middle section were calculated using an image tracking program (Noldus EthoVision XT). After the mice were given time to adapt to the new environment, each mouse was placed on the same corner and behavioral observation was started to trace the movement path. In order to prevent the mouse from exhibiting unwanted freezing behavior due to factors outside the experiment, this experiment was conducted in a quiet and dark room.
운동(Locomotor)의 경우 열린 공간 실험에서의 이동 거리로 측정하였으며, 불안 수준(Anxiety level)은 열린 공간 실험에서의 중간 체류(Center duration) 시간을 통해 측정하였다. In the case of locomotor, the movement distance in the open space experiment was measured, and the anxiety level was measured through the center duration time in the open space experiment.
또한, 알츠하이머 유도 및 chemical 투여에 따른 운동기능을 확인하기 위해 로타로드 실험을 수행하였다. 로타로드 실험은 5일간 하루에 3번 진행하였고, 10분 동안 4 내지 40 rpm까지 가속하는 로드(rod)에 얼마나 잘 버티는지를 시간(latency)을 통해 확인하였다.In addition, a rotarod experiment was performed to confirm the motor function according to Alzheimer's induction and chemical administration. The rotarod experiment was conducted 3 times a day for 5 days, and it was confirmed through the latency how well it withstands the rod that accelerates to 4 to 40 rpm for 10 minutes.
그 결과, 도 10 및 도 11에 나타난 열린 공간 실험 및 도 12에 나타난 로타로드 실험에서 모두 WT-vehicle, WT-chemical, APP/PS1-vehicle, APP/PS1-chemical group 간의 유의미한 차이는 없었다.As a result, there was no significant difference between the WT-vehicle, WT-chemical, APP/PS1-vehicle, and APP/PS1-chemical groups in the open space experiment shown in FIGS. 10 and 11 and the rotarod experiment shown in FIG. 12 .
실시예 3-4. 사회성 개선 확인(3CT)Example 3-4. Confirmation of social improvement (3CT)
동물의 사회성을 확인하기 위해 3 챔버 테스트를 진행하였다. A three-chamber test was performed to confirm the sociality of the animal.
정상적인 사회성을 지닌 마우스는 사회적 선호도 (social preference) 비어있는 곳(E) 보다 마우스(stranger 1)에 관심을 보이고, 사회적 인지도 (social recognition) 이전에 만난 마우스(stranger 1) 보다 새로운 마우스(stranger 2)에 더 관심을 보이는 경향이 있지만, 사회성이 낮은 알츠하이머 마우스의 경우에는 사회적 선호도 (social preference)에서는 정상 마우스와 비슷한 경향을 보이지만, 사회적 인지도 (social recognition)에서는 그렇지 않은 경향을 보이는 바, 이를 이용한 실험이 3 챔버 테스트이다. 구체적으로, 비어있는 곳(E) 및 마우스(stranger 1)가 주어지거나(사회적 선호도; social preference) 또는 이전에 만난 마우스(stranger 1) 및 새로운 마우스(stranger 2)가 주어졌을 때(사회적 인지도; social recognition), 각 방에서 비어있는 곳(E), 마우스 (stranger 1 and stranger 2) 와 상호작용 (sniffing) 하는 시간을 측정하여, WT-vehicle, WT-chemical, APP/PS1-vehicle, APP/PS1-chemical 그룹의 사회성을 측정하였다.A mouse with normal sociality showed interest in the mouse (stranger 1) rather than the empty space (E) in social preference, and a new mouse (stranger 2) than a mouse (stranger 1) met before social recognition (social recognition) In the case of Alzheimer's mice, which tend to show more interest in It is a three-chamber test. Specifically, when an empty place (E) and a mouse (stranger 1) are given (social preference) or when a previously met mouse (stranger 1) and a new mouse (stranger 2) are given (social awareness; social recognition), an empty place in each room (E), and the time to interact (sniffing) with a mouse (
그 결과, 도 13에 나타난 바와 같이, 새로운 마우스(S1)와 비어있는 곳 (E) 중 새로운 마우스에 얼마나 더 관심을 보이는가를 측정하는 경우(사회적 선호도; social preference), WT-vehicle, WT-chemical, APP/PS1-vehicle, 및 APP/PS1- chemical 모든 그룹에서 비어있는 곳(E)에서 보다 새로운 마우스 S1과 상호작용 (sniffing) 하는 시간이 증가됨을 확인하였다. As a result, as shown in FIG. 13, when measuring how much more interest the new mouse shows among the new mouse (S1) and the empty place (E) (social preference), WT-vehicle, WT-chemical , APP/PS1-vehicle, and APP/PS1-chemical confirmed that the time to interact (sniffing) with the new mouse S1 was increased compared to the empty place (E) in all groups.
또한, 도 14에 나타난 바와 같이, 새로운 마우스 (S1)과 또 다른 새로운 마우스 (S2) 중 또 다른 새로운 마우스에 얼마나 더 관심을 보이는가를 측정하는 경우(사회적 선호도; social preference), AD-vehicle 그룹은 또 다른 새로운 마우스에 대한 선호도가 없었던 반면, AD-chemical group은 새로운 마우스보다 또 다른 새로운 마우스에 더 관심을 갖고 있음을 확인하였다.In addition, as shown in FIG. 14 , when measuring how much more interest is shown in another new mouse among a new mouse (S1) and another new mouse (S2) (social preference), the AD-vehicle group was While there was no preference for another new mouse, it was confirmed that the AD-chemical group was more interested in the new mouse than the new mouse.
상기 결과를 통해, 알츠하이머병 환자에서 나타나는 사회성의 결핍이 chemical에 의해 완화됨을 확인하였다.Through the above results, it was confirmed that the lack of sociality in Alzheimer's disease patients was alleviated by chemical.
모든 자료는 mean(S.E.M)으로 표시하였고, 실험 군 간의 차이는 two-way ANOVA를 이용하여 확인하였다. p>0.05인 경우는 통계적으로 차이가 있다고 판정하였다. p>0.05 ;*, P>0.01 ; **.p>0.001 ; ***, p>0.0001 ; ****, ns ; nonsignificantAll data were expressed as mean (S.E.M), and differences between test groups were confirmed using two-way ANOVA. In the case of p>0.05, it was determined that there was a statistical difference. p>0.05 ;*, P>0.01 ; **.p>0.001 ; ***, p>0.0001 ; ****, ns ; nonsignificant
실시예 3-5. 아밀로이드 플라크(amyloid plaque) 감소 확인Example 3-5. Confirmation of amyloid plaque reduction
WT-vehicle, WT-chemical, APP/PS1-vehicle, APP/PS1-chemical 그룹의 마우스 뇌에서 아밀로이드 플라크(amyloid plaque)의 발현 양을 볼 수 있는 thioflavin S staining을 하였다.Thioflavin S staining was performed to show the expression level of amyloid plaques in mouse brains of WT-vehicle, WT-chemical, APP/PS1-vehicle, and APP/PS1-chemical groups.
이를 위하여, 상기 실시예 3-2 내지 3-4의 실험을 수행한 후 도 6에 나타난 시기에 마우스를 희생시켰다(Mouse sac). WT-vehicle, Wt-chemical, APP/PS1-vehicle, 및 APP/PS1-chemcial 그룹의 마우스에 Avertin을 복강 주사하여 마취하고, PBS (Phosphate buffer, pH 7.4) 용액과 4% paraformaldehyde 용액을 순서대로 관류하여 고정하였다. 이후, 뇌를 꺼내어 4% 파라포름알데히드(paraformaldehyde)에 16시간 담가둔 다음, 뇌를 다시 30% 수크로스(sucrose)가 포함된 PBS에 3일간 담가두었다. 그 다음, 동결 박절기를 이용하여 40um 두께로 연속관상절편을 제작하였다. 이와 같이 절편 된 뇌에서 유래한 부유 절편(floating section)을 PBS에 10분씩 3회 세척하였다. 70% 에탄올, 80%에탄올을 순서대로 1분씩 배양 후, 1% Thioflavin S (Sigma-Aldrich) solution에 15분간 배양하였다. 다시, 80% 에탄올 및 70% 에탄올에 순서대로 1분간 배양한 다음 Thioflavin S로 염색이 된 부유 절편(floating section)을 슬라이드에 올려 놓았다. 슬라이드에 mounting solution (No DAPI)을 넣고 커버 글라스로 덮은 후, 공초점 현미경을 사용하여 마우스 뇌조직에서 아밀로이드 B 플라크(amyloid B plaque)를 관찰하였다. To this end, after performing the experiments of Examples 3-2 to 3-4, mice were sacrificed at the time shown in FIG. 6 (Mouse sac). Anesthetized mice of WT-vehicle, Wt-chemical, APP/PS1-vehicle, and APP/PS1-chemcial groups by intraperitoneal injection of Avertin, followed by perfusion with PBS (Phosphate buffer, pH 7.4) solution and 4% paraformaldehyde solution sequentially and fixed. Thereafter, the brain was taken out and immersed in 4% paraformaldehyde for 16 hours, and then the brain was again immersed in PBS containing 30% sucrose for 3 days. Then, using a frozen slicer, continuous coronal slices with a thickness of 40 μm were prepared. The floating section derived from the brain sectioned in this way was washed 3 times for 10 minutes in PBS. 70% ethanol and 80% ethanol were incubated for 1 minute in order, and then incubated in 1% Thioflavin S (Sigma-Aldrich) solution for 15 minutes. Again, incubated for 1 minute in 80% ethanol and 70% ethanol sequentially, and then a floating section stained with Thioflavin S was placed on a slide. After putting a mounting solution (No DAPI) on the slide and covering it with a cover glass, amyloid B plaques were observed in mouse brain tissue using a confocal microscope.
그 결과, 도 15에 나타난 바와 같이, APP/PS1-vehicle 그룹의 마우스 뇌조직에 비해 APP/PS1-chemical group의 마우스 뇌조직에서 아밀로이드 B 플라크(amyloid B plaque)가 적게 관찰됨을 확인하였다.As a result, as shown in FIG. 15 , it was confirmed that less amyloid B plaques were observed in the mouse brain tissue of the APP/PS1-chemical group compared to the mouse brain tissue of the APP/PS1-vehicle group.
실시예 3-6. 면역조직화학적 분석Example 3-6. Immunohistochemical analysis
실시예 3-5와 마찬가지로, 희생시킨 마우스에서 뇌를 적출한 후, MeCP2 저해제 화합물이 실제로 마우스 뇌에서 MeCP2를 감소시키는지 여부를 확인하기 위해 MeCP2에 대한 IHC를 수행하였다. 그리고 알츠하이머병 질병 모델의 마우스에서 관찰되는 신경세포의 사멸을 관찰하기 위해, 신경세포 마커인 NeuN을 이용하여 IHC를 진행하였다. 실험은 알츠하이머병의 주요 뇌 부위인 해마 (hippocampus) 내 배측 해마 (dorsal hippocampus), 후각 피질(Entorhinal cortex), 복측 해마 (Ventral hippocampus) 조직 및 복측 선조체(Ventral striatum) 조직을 대상으로 진행하였다.As in Example 3-5, after brain extraction from sacrificial mice, IHC for MeCP2 was performed to confirm whether the MeCP2 inhibitor compound actually reduced MeCP2 in the mouse brain. And Alzheimer's disease In order to observe the death of neurons observed in the mouse of the disease model, IHC was performed using the neuronal marker NeuN. The experiment was conducted with tissues of the dorsal hippocampus, entorhinal cortex, ventral hippocampus, and ventral striatum within the hippocampus, which are major brain regions of Alzheimer's disease.
구체적으로, 실시예 3-5에서 만들어진 40um 두께의 연속관상절편을 이용하였다. 절편된 뇌에서 유래한 부유 절편(floating section)을 TBS (Tris-Buffered saline, pH 7.4)에 10분씩 3회 세척 후, TBST (0.3% Triton-X100 (Sigma Aldrich) in TBS)에 10분씩 3회 세척하였다. NDS(normal donkey serum)를 TBST 용액에 5%가 되도록 만들어진 용액에 상온에서 한 시간 동안 배양하여 blocking 진행 후, mouse anti-NeuN (Millipore, 1:200)항체와 rabbit anti-MeCP2 (Millipore, 1:250) 항체를 넣은 1% NDS in TBST 용액을 이용하여 4도에서 이틀간 배양하였다. 그 후 TBST 용액에서 10분씩 3번 세척 후, donkey anti-mouse, Alexa Fluor 594 (Invitrogen; 1:400)과 donkey anti-rabbit, 및 Alexa Fluor 488 (Invitrogen; 1:400) 항체를 넣은 1% NDS in TBST 용액을 이용하여 상온에서 두 시간 배양하였다. 그 후, TBST용액에서 10분씩 3번 세척한 다음 항체를 이용하여 염색된 부유 절편(floating section)을 슬라이드에 올려 놓았다. 슬라이드에 DAPI가 포함된 mounting solution을 넣고 커버 글라스로 덮은 후, 공초점 현미경을 이용하여 마우스의 뇌조직에서 MeCP2 (488-green), NeuN (594-red), 및 DAPI(405-blue)를 관찰하였다. Specifically, a continuous coronal section with a thickness of 40 μm made in Examples 3-5 was used. Floating sections derived from the sectioned brain were washed 3 times for 10 minutes in TBS (Tris-Buffered saline, pH 7.4), then 3 times for 10 minutes in TBST (0.3% Triton-X100 (Sigma Aldrich) in TBS) washed. After blocking by incubating NDS (normal donkey serum) in a solution made to 5% in TBST solution at room temperature for one hour, mouse anti-NeuN (Millipore, 1:200) antibody and rabbit anti-MeCP2 (Millipore, 1: 250) using a 1% NDS in TBST solution containing the antibody, and incubated at 4°C for two days. After washing 3 times for 10 minutes in TBST solution, 1% NDS containing donkey anti-mouse, Alexa Fluor 594 (Invitrogen; 1:400) and donkey anti-rabbit, and Alexa Fluor 488 (Invitrogen; 1:400) antibodies in TBST solution was incubated for two hours at room temperature. Then, after washing 3 times for 10 minutes in TBST solution, the floating section stained with the antibody was placed on the slide. Put the mounting solution containing DAPI on the slide, cover it with a cover glass, and observe MeCP2 (488-green), NeuN (594-red), and DAPI (405-blue) in the mouse brain tissue using a confocal microscope. did.
그 결과, 도 16, 도 17, 도 18, 및 도 19에 나타난 바와 같이, WT-vehicle과 APP/PS1-vehicle 그룹에 비해 WT-chemcial과 APP/PS1-chemical 그룹에서 MeCP2의 발현량이 감소됨을 확인하였다. 또한, APP/PS1-vehicle 그룹의 마우스 조직에서 NeuN의 발현이 다른 그룹에 비해 감소됨을 확인하였다. 그러나, APP/PS1-chemical 그룹에서는 APP/PS1-vehicle 그룹에 비해 NeuN을 발현하는 신경세포들이 많음을 확인하였다.As a result, as shown in FIGS. 16, 17, 18, and 19, it was confirmed that the expression level of MeCP2 was reduced in the WT-chemcial and APP/PS1-chemical groups compared to the WT-vehicle and APP/PS1-vehicle groups. did. In addition, it was confirmed that the expression of NeuN in the mouse tissue of the APP/PS1-vehicle group was reduced compared to other groups. However, it was confirmed that there were more NeuN-expressing neurons in the APP/PS1-chemical group than in the APP/PS1-vehicle group.
상기 결과로부터, 본 발명에서 1-페닐-3-{6-[3-(트리플루오로메틸)페녹시]피리딘-3-닐}유레아는 알츠하이머 병 질병 마우스 모델인 APP/PS1의 뇌에서 감소한 신경세포를 증가시키는 등 퇴행성 뇌질환을 효과적으로 치료할 수 있음을 확인하였다.From the above results, in the present invention, 1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea has reduced neurons in the brain of APP/PS1, an Alzheimer's disease mouse model. It was confirmed that it can effectively treat degenerative brain diseases such as increasing cells.
이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, those skilled in the art to which the present invention pertains will be able to understand that the present invention may be embodied in other specific forms without changing the technical spirit or essential characteristics thereof. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention, rather than the above detailed description, all changes or modifications derived from the meaning and scope of the claims described below and their equivalents.
Claims (9)
1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}urea (1-phenyl-3-{6-[3-(trifluoromethyl)phenoxy]pyridin-3- yl}urea) compound or a pharmaceutically acceptable salt thereof.
A composition for inhibiting MeCP2 (Methyl-CpG-binding protein 2) comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition for preventing or treating degenerative brain disease comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
The pharmaceutical composition of claim 3, wherein the composition further comprises a pharmaceutically acceptable carrier, excipient, or diluent.
The pharmaceutical composition of claim 3, wherein the degenerative brain disease is at least one selected from the group consisting of Parkinson's disease, Alzheimer's disease, senile dementia, memory impairment, and memory loss.
A food composition for preventing or improving degenerative brain disease comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
A quasi-drug composition for preventing or improving degenerative brain disease, comprising the compound of claim 1 or a quasi-pharmaceutically acceptable salt thereof as an active ingredient.
A feed composition for preventing or improving degenerative brain disease, comprising the compound of claim 1 or a fodder acceptable salt thereof as an active ingredient.
A method for preventing or treating Alzheimer's disease comprising administering the pharmaceutical composition of claim 3 to a subject other than a human.
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WO2007149395A2 (en) * | 2006-06-20 | 2007-12-27 | Amphora Discovery Corporation | 2,5-substituted oxazole derivatives as protein kinase inhibitors for the treatment of cancer |
KR102052097B1 (en) * | 2017-11-30 | 2019-12-05 | 한국과학기술연구원 | Composition comprising MECP2 protein or polynucleotide encoding the MECP2 for prevention and treatment of of neurodegenerative disease |
KR20210018267A (en) * | 2018-05-07 | 2021-02-17 | 알닐람 파마슈티칼스 인코포레이티드 | Extrahepatic delivery |
CA3111392A1 (en) * | 2018-09-04 | 2020-03-12 | Magenta Therapeutics, Inc. | Aryl hydrocarbon receptor antagonists and methods of use |
-
2022
- 2022-03-23 WO PCT/KR2022/004080 patent/WO2022203395A1/en active Application Filing
- 2022-03-23 KR KR1020220036316A patent/KR20220132477A/en unknown
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