KR20220124557A - Compound for cyp1a inhibition and cyp1a inhibition material comprising the same - Google Patents
Compound for cyp1a inhibition and cyp1a inhibition material comprising the same Download PDFInfo
- Publication number
- KR20220124557A KR20220124557A KR1020210028379A KR20210028379A KR20220124557A KR 20220124557 A KR20220124557 A KR 20220124557A KR 1020210028379 A KR1020210028379 A KR 1020210028379A KR 20210028379 A KR20210028379 A KR 20210028379A KR 20220124557 A KR20220124557 A KR 20220124557A
- Authority
- KR
- South Korea
- Prior art keywords
- compound
- cyp1a
- present
- cyp1a2
- inhibiting
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Abstract
Description
본 발명은 CYP1A 억제용 화합물 및 이를 포함한 CYP1A 억제용 조성물에 관한 것이다.The present invention relates to a compound for inhibiting CYP1A and a composition for inhibiting CYP1A including the same.
생물은 이물질이 체내로 유입되었을 때 여러 생체적인 메카니즘을 작동시켜 유입된 이물질을 대사시키든지 외부로 배출시키려고 한다. 약물도 마찬가지로 인체내로 투여되었을 때 대사되거나 외부로 배출되려는 경향이 있다. 대부분의 약물의 경우 그것이 인체에 투여되었을 때 그것이 인체에서 얼마나 오랫동안 그리고 얼마나 높은 농도로 유지될 수 있는가는 그것의 대사에 관여하는 약물 대사 효소에 의하여 결정되게 된다. 이러한 약물 대사 효소로는 사이토크롬 P450(Cytochrome P450) 초계열(Suprefamily)의 효소, N-아세틸 전이효소(NAcetyl Transferase), UDP-글루쿠론산 전이효소(UDP-Glucuronosyl Transferase), 메틸 전이효소(Methy Transferase), 알콜 탈수소화효소(Alcohol Dehydrogenase), 알데하이드 탈수소화효소(Aldehyde Dehydrogenase) 등을 들 수 있다.When a foreign material is introduced into the body, living organisms try to metabolize the foreign material or expel it to the outside by operating various biological mechanisms. Drugs also tend to be metabolized or excreted when administered into the human body. For most drugs, when administered to the human body, how long and how high the concentration can be maintained in the human body is determined by the drug metabolizing enzymes involved in its metabolism. Examples of such drug metabolizing enzymes include cytochrome P450 (Suprefamily) enzymes, N-acetyl transferase (NAcetyl Transferase), UDP-glucuronosyl transferase (UDP-Glucuronosyl Transferase), methyl transferase (Methy) Transferase), alcohol dehydrogenase, aldehyde dehydrogenase, and the like.
또한, 신약 후보물질로 합성되는 화합물을 개발하기 위해서는 약물 상호작용에 대한 검색이 필요하고 이 과정을 효율적으로 수행하기 위한 약물 대사효소 활성 검색기술의 확립은 필수적이다. 대부분의 임상학적으로 중요한 약물상호 작용은 간의 사이토크롬(P450) 효소와 관계되며, 여러 종류의 동종효소(아이소자임, isozyme)가 약물의 대사에 관여한다. 한 가지, 혹은 여러 가지 사이토크롬 P450 효소의 가역적 저해로 인한 약물 상호작용은 신약 후보 물질이 개발 과정에서 탈락되는 큰 원인 중 하나이고, 지난 몇 년간 임상 시험과정 중 약물의 사용을 제한하게 되는 주요 원인이 되었다(Lin JH et al, 2002). 이를 극복하기 위해 사람 간 마이크로좀과 기질 약물을 이용하여 시험관 내(in vitro) 약물 상호작용의 검색은 1990년대 이후로 지속적으로 증가하고 있다.In addition, in order to develop a compound synthesized as a new drug candidate, it is necessary to search for drug interactions, and it is essential to establish a drug metabolizing enzyme activity screening technology to efficiently perform this process. Most clinically important drug interactions are related to hepatic cytochrome (P450) enzymes, and several types of isoenzymes (isozymes) are involved in drug metabolism. Drug interactions due to the reversible inhibition of one or several cytochrome P450 enzymes are one of the major causes of drug candidates dropping out in the development process, and the main reason for limiting the use of drugs during clinical trials over the past few years. (Lin JH et al, 2002). To overcome this, the search for in vitro drug interactions using human microsomes and substrate drugs has been continuously increasing since the 1990s.
사이토크롬 P450 (Cytochrome P450; 이하 "CYP") 효소는 간이나 신장 등에서 수많은 약물의 대사를 담당하는데, 상기 단계 °의 효소에 해당한다. CYP 초계열의 효소는 친유성 화합물(Lipophilic Compound)의 산화 반응과 탈수소화 반응을 촉매하는 헴 단백질(Heme Protein)을 지니고 있다. 적어도 약 30 여종의 효소가 이러한 CYP 초계열의 효소에 속하는 것으로 알려지고 있다. 이들 효소들은 그들이 가지는 아미노산 서열 상동성에 따라서 몇 가지 계열(Family)로 나누어지는데, CYP1, CYP2, CYP3, CYP4 계열 효소로 분류된다.Cytochrome P450 (hereinafter "CYP") enzyme is responsible for the metabolism of numerous drugs in the liver or kidney, etc., and corresponds to the enzyme in step °. CYP superfamily enzymes have a heme protein that catalyzes the oxidation and dehydrogenation reactions of lipophilic compounds. At least about 30 enzymes are known to belong to this superfamily of CYP enzymes. These enzymes are divided into several families according to their amino acid sequence homology, and are classified into CYP1, CYP2, CYP3, and CYP4 family enzymes.
이에 본 발명자들은 다른 CYP subfamily에 영향 없이 CYP1A 효소의 활성만을 선택적으로 억제하는 CYP1A 선택적 억제제에 대해 연구한 결과 본 발명을 완성하였다. Accordingly, the present inventors completed the present invention as a result of studying a CYP1A selective inhibitor that selectively inhibits only the CYP1A enzyme activity without affecting other CYP subfamily.
본 발명의 일 양상은 화학식 1로 표현되는 화합물을 포함하는 CYP1A (Cytochrome P450 subfamily 1A) 억제용 화합물을 제공하는 것을 목적으로 한다.One aspect of the present invention aims to provide a compound for inhibiting CYP1A (Cytochrome P450 subfamily 1A), including the compound represented by Formula 1.
본 발명의 다른 일 양상은 상기 화합물을 포함하는 CYP1A (Cytochrome P450 subfamily 1A) 억제용 조성물을 제공하는 것을 목적으로 한다.Another aspect of the present invention aims to provide a composition for inhibiting CYP1A (Cytochrome P450 subfamily 1A) comprising the compound.
본 발명의 일 양상은 하기 화학식 1로 표현되는 화합물을 포함하는 CYP1A (Cytochrome P450 subfamily 1A) 억제용 화합물을 제공한다:One aspect of the present invention provides a compound for inhibiting CYP1A (Cytochrome P450 subfamily 1A) comprising a compound represented by the following Chemical Formula 1:
[화학식 1] [Formula 1]
상기 화학식 1에서In Formula 1 above
X는 C, O 또는 S중 어느 하나이고,X is any one of C, O or S,
A는 히드록시기 또는 탄소원자가 1-6인 직쇄 혹은 분쇄 알콕시 중 하나이다.A is either a hydroxy group or a straight-chain or branched alkoxy having 1-6 carbon atoms.
구체적으로, 상기 식에서 X는 C 또는 O이고, A는 히드록시기 또는 메톡시일 수 있다. Specifically, in the above formula, X may be C or O, and A may be a hydroxy group or methoxy.
상기 CYP1A 는 약물대사효소인 cytochrome P450(CYP)의 아형 중 하나로서 상기 cytochrome P450(CYP)는 상용화된 약물 70% 이상의 대사를 담당하는 핵심적인 임무를 수행한다. 상기 CYP1A는 사람의 간에서 전체 CYP대비 약 13%를 차지하는 중요한 대사효소이다. CYP1A은 CYP1A1과 CYP1A2의 세부 아형으로 구성되고, 다양한 약물성 기질을 가지고 있는데, 타이레놀의 성분인 acetaminophen이 대표적이다. 신약개발과정 중에 후보물질에 대사에 관여하는 CYP효소의 아형에 대한 작용을 규명하는 것은 약물상호작용을 예측하는데 필수적인 과정이다. 함께 복용하는 약이 같은 대사효소를 공유하거나, 활성을 조절한다면 혈중농도의 변화로 인해 약효소실 또는 독성발현과 같은 부작용을 초래할 수 있기 때문이다. The CYP1A is one of the subtypes of cytochrome P450 (CYP), which is a drug metabolizing enzyme, and the cytochrome P450 (CYP) performs a key task responsible for the metabolism of more than 70% of the commercialized drug. The CYP1A is an important metabolic enzyme that accounts for about 13% of the total CYP in the human liver. CYP1A is composed of subtypes of CYP1A1 and CYP1A2 and has various pharmacological substrates, and acetaminophen, a component of Tylenol, is representative. Identification of the action on the subtype of the CYP enzyme involved in the metabolism of candidate substances during the process of drug development is an essential process for predicting drug interactions. This is because, if drugs taken together share the same metabolic enzyme or regulate activity, side effects such as drug enzyme room or toxicity can occur due to changes in blood concentration.
본 발명의 일 구체예로서, 상기 화학식 1의 화합물은 아래의 화합물 1 내지 4중 어느 하나이다:In one embodiment of the present invention, the compound of Formula 1 is any one of
[화합물 1] [Compound 1]
[화합물 2] [Compound 2]
[화합물 3] [Compound 3]
[화합물 4] [Compound 4]
상기 화합물 1 은 2,3-디하이드로-2-[(3-히드록시페닐)메틸렌]-1H-인덴-1-온 (2,3-Dihydro-2-[(3-hydroxyphenyl)methylene]-1H-inden-1-one)이고, 화합물 2는 2,3-디하이드로-2-[(3-메톡시페닐)메틸렌]-1H-인덴-1-온 (2,3-Dihydro-2-[(3-methoxyphenyl)methylene]-1H-inden-1-one)이고, 화합물 3은 2-[(3-히드록시페닐)메틸렌]-3(2H)-벤조퓨란온(2-[(3-Hydroxyphenyl)methylene]-3(2H)-benzofuranone)이며, 화합물 4는 2-[(3-메톡시페닐)메틸렌]-3(2H)-벤조퓨란온 (2-[(3-Methoxyphenyl)methylene]-3(2H)-benzofuranone) 이다. The
본 발명의 상기 화합물은 CYP1A, 구체적으로 CYP1A1 및 CYP1A2, 의 활성을 선택적으로 억제하는 것을 확인하였고, 이러한 효능을 이용하여 약물상호작용 평가 시 표준억제제로 활용이 가능하다. It was confirmed that the compound of the present invention selectively inhibits the activity of CYP1A, specifically CYP1A1 and CYP1A2, and can be used as a standard inhibitor when evaluating drug interactions using this efficacy.
본 발명의 다른 일 양상은 상기 화합물을 포함하는 CYP1A (Cytochrome P450 subfamily 1A) 억제용 조성물을 제공한다.Another aspect of the present invention provides a composition for inhibiting CYP1A (Cytochrome P450 subfamily 1A) comprising the compound.
전술한 바와 같이 상기 화합물은 화학식 1로 표현되는 화합물, 구체적으로는 화합물 1 내지 4 중 어느 하나로서 상기 화합물 1 은 2,3-디하이드로-2-[(3-히드록시페닐)메틸렌]-1H-인덴-1-온 (2,3-Dihydro-2-[(3-hydroxyphenyl)methylene]-1H-inden-1-one)이고, 화합물 2는 2,3-디하이드로-2-[(3-메톡시페닐)메틸렌]-1H-인덴-1-온 (2,3-Dihydro-2-[(3-methoxyphenyl)methylene]-1H-inden-1-one)이고, 화합물 3은 2-[(3-히드록시페닐)메틸렌]-3(2H)-벤조퓨란온(2-[(3-Hydroxyphenyl)methylene]-3(2H)-benzofuranone)이며, 화합물 4는 2-[(3-메톡시페닐)메틸렌]-3(2H)-벤조퓨란온 (2-[(3-Methoxyphenyl)methylene]-3(2H)-benzofuranone) 이다.As described above, the compound is a compound represented by
본 발명의 일 구체예로서, 상기 CYP1A는 CYP1A1 및 CYP1A2 중 어느 하나 이상이다.In one embodiment of the present invention, the CYP1A is any one or more of CYP1A1 and CYP1A2.
전술한 바와 같이 CYP1A는 약물대사효소인 cytochrome P450(CYP)의 아형 중 하나이고, CYP1A은 CYP1A1과 CYP1A2의 세부 아형이다. CYP1A2는 아세트아미노펜 (acetaminophen), 아미트립틸린 카페인 (amitriptyline caffeine), 클로자핀(clozapine), 할로페리돌 (haloperidol), 이미프라민 (imipramine), 올란자핀 (olanzapine), 온단스테론(ondansetron), 페나세틴(phenacetin), 프로파페논(propafenone), 프로판올롤(propranolol), 타크린(tacrine), 테오필린(theophylline) 및 베라파밀 (verapamil)을 대사하는 효소로 알려져 있다. As described above, CYP1A is one of the subtypes of cytochrome P450 (CYP), a drug metabolizing enzyme, and CYP1A is a subtype of CYP1A1 and CYP1A2. CYP1A2 contains acetaminophen, amitriptyline caffeine, clozapine, haloperidol, imipramine, olanzapine, ondansetron, and phenacetin. ), propafenone, propranolol, tacrine, theophylline, and verapamil are known to metabolize enzymes.
본 발명의 조성물은 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다. 포함될 수 있는 담체, 부형제 및 희석제로는 락토오스, 덱스트로오스, 수크로오스, 소르비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘포스페이트, 칼슘 실리 케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 물, 메틸히드록시 벤조에이트, 프로필히드록시 벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등이 있다.The composition of the present invention may further include suitable carriers, excipients and diluents commonly used. Carriers, excipients and diluents that may be included include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, undecided. vaginal cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate and mineral oil.
또한, 본 발명의 조성물은 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 상기 조성물을 제제 화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 조성물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트 (calcium carbonate), 수크로오스, 락토오스, 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 있으며, 흔히 사 용되는 단순 희석제인 물, 리퀴드 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 가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다.In addition, the composition of the present invention can be formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injection solutions according to conventional methods. . When formulating the composition, it is usually prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the composition, for example, starch, calcium carbonate, sucrose, lactose, It is prepared by mixing gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include suspensions, solutions, emulsions, syrups, etc., and various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included in addition to commonly used simple diluents such as water and liquid paraffin. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, and freeze-dried preparations. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
본 발명의 일 구체예로서, 상기 조성물은 약물상호작용 평가용일 수 있다. In one embodiment of the present invention, the composition may be for drug interaction evaluation.
상기 약물상호작용은 2종류 이상의 약물을 적용하는 경우에 발생하는 약물간의 작용으로, 약물의 성분이나 흡수, 기전, 작용 대상 및 질환에 따라 약물의 효과가 증감될 수 있다. 구체적으로, 약물을 병용한 경우 각각 단독으로 이용한 경우보다도 효과가 클 때는 협력(Synergy)이라고 하고, 약물들이 서로 작용을 상쇄하는 경우를 길항(antagonism)이라한다. The drug interaction is an action between drugs that occurs when two or more kinds of drugs are applied, and the effect of the drug may be increased or decreased depending on the component, absorption, mechanism, action target, and disease of the drug. Specifically, when drugs are used in combination, when the effect is greater than when each drug is used alone, it is called synergy, and when drugs cancel each other's action, it is called antagonism.
약물상호작용 평가에서는 이러한 약물들 간의 상호작용을 평가하는데, 각각의 CYP1A에 대한 선택적 억제제의 사용이 필수적으로 요구된다. 구체적으로, CYP1A에 작용하는 공지의 약물과의 상호작용을 평가하기 위해서는 공지의 약물 처리에 따른 CYP1A 작용을 고려하여, CYP1A의 작용을 억제시킨 조건에서 시험 대상 약물의 작용을 평가하여야 하기 때문에, CYP1A를 억제할 수 있는 본 발명의 화합물은 약물상호작용 평가에 사용될 수 있다. Drug interaction evaluation evaluates the interaction between these drugs, and the use of selective inhibitors for each CYP1A is essential. Specifically, in order to evaluate the interaction with a known drug acting on CYP1A, it is necessary to evaluate the action of the test drug under conditions in which the action of CYP1A is inhibited, considering the action of CYP1A following treatment with the known drug. The compound of the present invention capable of inhibiting the drug may be used for drug interaction evaluation.
본 발명의 CYP1A 억제용 화합물 및 이를 포함한 CYP1A 억제용 조성물은 CYP1A, 구체적으로 CYP1A1 및 CYP1A2의 활성을 선택적으로 억제하여 약물상호작용 평가 시 표준억제제로 활용이 가능하다. The compound for inhibiting CYP1A of the present invention and the composition for inhibiting CYP1A including the same selectively inhibit the activity of CYP1A, specifically CYP1A1 and CYP1A2, so that it can be used as a standard inhibitor when evaluating drug interactions.
도 1은 본 발명 화합물의 CYP2C8에 대비 CYP1A2에 대한 선택적 억제 효과 및 경쟁적 억제효과를 나타내는 도면이다.
도 2는 본 발명 화합물의 Lineweaver-Burk plots을 통한 경쟁적 억제기전 검증 및 Ki값을 나타내는 도면이다.
도 3은 본 발명 화합물의 농도 별 CYP1A의 아형효소인 CYP1A1 및 CYP1A2에 대한 억제효과를 나타내는 도면이다.1 is a diagram showing the selective inhibitory effect and the competitive inhibitory effect on CYP1A2 compared to CYP2C8 of the compound of the present invention.
2 is a view showing the competitive inhibition mechanism verification and Ki values through Lineweaver-Burk plots of the compounds of the present invention.
3 is a diagram showing the inhibitory effect on CYP1A1 and CYP1A2, which are subtype enzymes of CYP1A, according to the concentration of the compound of the present invention.
이하 하나 이상의 구체예를 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 하나 이상의 구체예를 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, one or more specific examples will be described in more detail through examples. However, these examples are for illustrative purposes of one or more embodiments, and the scope of the present invention is not limited to these examples.
실시예 1: 본 발명 화합물의 준비Example 1: Preparation of the compound of the present invention
본 발명의 화합물 1 내지 4는 영남대학교 이응석 교수팀으로부터 입수하여 준비하였다.
실시예 2: 본 발명 화합물의 CYP 억제 효과 확인Example 2: Confirmation of the CYP inhibitory effect of the compound of the present invention
실시예 1에서 준비된 화합물 1 내지 4의 CYP 억제능을 확인하였다. The CYP inhibitory ability of
CYP 억제능을 확인하기 위해 화합물 1 내지 4를 0- 50 uM 농도로 사람간 마이크로좀 (human liver microsome, HLM)내에서 9가지 CYP효소의 기질과 반응시켰다. 각 9개의 CYP의 활성측정을 위한 선택적 기질로 phenacetin (CYP1A2), coumarin (CYP2A6), bupropion (CYP2B6), paclitaxel (CYP2C8), diclofenac (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1), and midazolam (CYP3A4)를 사용하였다. 각 반응액은 최종 배양 부피 0.1 mL에 대해 50μg HLM, β-NADPH 생성 시스템 (NGS, 0.1M glucose 6-phosphate, 10 mg/ml β-ADPH, 1.0 U/ml glucose-6-phosphate dehydrogenase), 9개의 CYP기질 혼합물고 구성되었다. 5분 동안 사전 배양 한 후 NGS를 추가하여 37도에서 60분 동안 반응 후 0.1% 개미산을 함유하는 100 ul의 아세토니트릴과 내부 표준 용액 (10 μM reserpine) 5 ul를 첨가하여 반응을 종결 시켰다. 13,000g 에서 5 분간 혼합 및 원심분리 한 후, LC-MS/MS을 통해 검출되는 각 CYP기질 대사체의 크로마토그램 상 피크의 면적을 계산하여 활성을 측정하였다. In order to confirm the CYP inhibitory ability, compounds 1 to 4 were reacted with the substrates of 9 CYP enzymes in human liver microsome (HLM) at a concentration of 0-50 uM. phenacetin (CYP1A2), coumarin (CYP2A6), bupropion (CYP2B6), paclitaxel (CYP2C8), diclofenac (CYP2C9), chlorzoxazole (CYP2C19), dextromethorphan1 (CYP2D6), ), and midazolam (CYP3A4) were used. Each reaction solution contains 50 μg HLM, β-NADPH generating system (NGS, 0.1M glucose 6-phosphate, 10 mg/ml β-ADPH, 1.0 U/ml glucose-6-phosphate dehydrogenase), 9 for a final culture volume of 0.1 mL. It consisted of a mixture of two CYP substrates. After pre-incubation for 5 minutes, NGS was added and reacted at 37 degrees for 60 minutes. Then, 100 ul of acetonitrile containing 0.1% formic acid and 5 ul of an internal standard solution (10 μM reserpine) were added to terminate the reaction. After mixing and centrifugation at 13,000 g for 5 minutes, activity was measured by calculating the area of the peak on the chromatogram of each CYP substrate metabolite detected through LC-MS/MS.
그 결과, 표 1과 같이 본 발명의 화합물 1 내지 4는 CYP1A, 구체적으로 CYP1A2의 억제능이 우수한 것을 확인하였다. 또한, 화합물 4 (HYIpro-3-1)이 가장 우수한 CYP1A2 억제능을 가진 것을 확인하여 이하에서는 화합물 4를 이용하여 실험하였다. As a result, as shown in Table 1, it was confirmed that
실시예 3: 본 발명 화합물의 CYP1A 선택적 억제능 확인Example 3: Confirmation of selective CYP1A inhibitory ability of the compound of the present invention
본 발명 화합물의 다른 CYP 대비 CYP1A의 선택적 억제능을 확인하였다.The selective inhibitory ability of CYP1A compared to other CYPs of the compound of the present invention was confirmed.
CYP1A2에 대해 억제효과의 검증하고 기전을 확인하기 위한 실험을 3개 조건으로 구분하여 수행하였다. (1) 화합물 4 (0-2.5 uM), HLM (0.5 mg/ml), CYP1A2 기질, NGS를 한꺼번에 혼합하여 37도에서 60분간 반응; (2) 화합물4 (0-2.5 uM)을 HLM (0.5 mg/ml)과 혼합 후 5분간 사전배양 후 NGS와 CYP1A2 기질을 혼합하여 37도에서 60분간 반응; (3) 화합물 4 (0-2.5 uM), HLM (0.5 mg/ml)과 NGS를 혼합 후 5분간 사전배양 후 CYP1A2기질을 혼합하여 37도에서 60분간 반응. 같은 조건으로 CYP2C8에 대한 억제효과를 관찰하였다. Experiments to verify the inhibitory effect on CYP1A2 and to confirm the mechanism were performed by dividing it into three conditions. (1) Compound 4 (0-2.5 uM), HLM (0.5 mg/ml), CYP1A2 substrate, and NGS were mixed together and reacted at 37°C for 60 minutes; (2) Compound 4 (0-2.5 uM) was mixed with HLM (0.5 mg/ml) and pre-incubated for 5 minutes, then NGS and CYP1A2 substrate were mixed and reacted at 37°C for 60 minutes; (3) Compound 4 (0-2.5 uM), HLM (0.5 mg/ml) and NGS were mixed and pre-incubated for 5 minutes. Then, CYP1A2 substrate was mixed and reacted at 37°C for 60 minutes. Inhibitory effect on CYP2C8 was observed under the same conditions.
그 결과, 본 발명 화합물은 다른 CYP (CYP2C8)에 대하여 1μM 이상 고농도 처리시에만 활성 억제능을 보이나, CYP1A (CYP1A2)에 대해서는 0.1μM 이상에서도 활성 억제능을 확인할 수 있다 (도 1 참조). 그 억제기전은 경쟁적억제 (competitive inhibition)으로 추정되었다. As a result, the compound of the present invention exhibits activity inhibiting ability only at high concentrations of 1 μM or more with respect to other CYP (CYP2C8), but activity inhibiting ability can be confirmed even at 0.1 μM or more with respect to CYP1A (CYP1A2) (see FIG. 1). The inhibitory mechanism was presumed to be competitive inhibition.
또한, 화합물 4의 CYP1A에 대한 억제기전을 규명하기 위해 Michaelis-Menten equation 및 Lineweaver-Burk plot을 설정하였다. 화합물 4의 반응액내 농도를 0, 0.05, 0.1 및 0.2 uM로 설정하고, CYP1A2 기질인 phenacetin을 40, 80, 120, 400 uM로 설정하였다. 화합물 4의 농도에 따라 다른 농도의 기질액을 혼합 후 HLM (0.5 mg/ml)가 NGS를 첨가하고 37도에서 60분간 반응하였다. LC-MS/MS를 통해 생성되는 대사체의 피크 면적을 계산하여 억제능을 관찰하였다. Lineweaver-Burk plot 결과에 따라 화합물 4는 CYP1A2에 대한 competitive inhibition을 나타내었다. In addition, the Michaelis-Menten equation and Lineweaver-Burk plot were set up to investigate the inhibitory mechanism of compound 4 on CYP1A. The concentration of compound 4 in the reaction solution was set to 0, 0.05, 0.1 and 0.2 uM, and the CYP1A2 substrate phenacetin was set to 40, 80, 120, and 400 uM. After mixing the substrate solution of different concentrations according to the concentration of compound 4, HLM (0.5 mg/ml) was added with NGS and reacted at 37°C for 60 minutes. The inhibitory ability was observed by calculating the peak area of the metabolite produced through LC-MS/MS. According to the Lineweaver-Burk plot result, compound 4 showed competitive inhibition against CYP1A2.
실시예 4: 본 발명 화합물의 CYP1A 억제 효과 확인Example 4: Confirmation of the CYP1A inhibitory effect of the compound of the present invention
본 발명 화합물의 농도별 CYP1A의 아형 효소인 CYP1A1 및 CYP1A2 억제능을 확인하였다.The inhibitory ability of CYP1A1 and CYP1A2 subtype enzymes of CYP1A was confirmed by concentration of the compound of the present invention.
CYP1A의 아형 효소에서의 화합물 4의 억제능을 검증하기 위해, 화합물 4를 0-10 uM 농도범위로, 인간 재조합 cDNA 발현 CYP1A1 및 CYP1A2 (10 pmole), CYP1A2 기질, NGS를 혼합하여 37도에서 60분간 반응 후 화합물 4의 CYP1A1 및 CYP1A2에 대한 활성 억제능을 평가하였다.To verify the inhibitory ability of compound 4 in the subtype enzyme of CYP1A, compound 4 was mixed in a concentration range of 0-10 uM, human recombinant cDNA expression CYP1A1 and CYP1A2 (10 pmole), CYP1A2 substrate, and NGS at 37°C for 60 minutes. After the reaction, the activity inhibitory ability of Compound 4 on CYP1A1 and CYP1A2 was evaluated.
그 결과, 도 3에서 확인되는 바와 같이, 본 발명 화합물은 0.5 μM 수준에서 CYP1A1 및 CYP1A2의 억제능이 있음을 확인하였다.As a result, as confirmed in FIG. 3 , it was confirmed that the compound of the present invention had inhibitory ability of CYP1A1 and CYP1A2 at a level of 0.5 μM.
이러한 결과를 통해 본 발명의 화합물은 CYP1A, 구체적으로 CYP1A1 및 CYP1A2, 의 활성을 선택적으로 억제하여 약물상호작용 평가 시 표준억제제로 활용이 가능함을 확인하였다.Through these results, it was confirmed that the compound of the present invention selectively inhibits the activity of CYP1A, specifically CYP1A1 and CYP1A2, and thus can be used as a standard inhibitor when evaluating drug interactions.
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far, with respect to the present invention, the preferred embodiments have been looked at. Those of ordinary skill in the art to which the present invention pertains will understand that the present invention may be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments are to be considered in an illustrative rather than a restrictive sense. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.
Claims (5)
[화학식 1]
상기 화학식 1에서
X는 C, O 또는 S중 어느 하나이고,
A는 히드록시기 또는 탄소원자가 1-6인 직쇄 혹은 분쇄 알콕시 중 하나이다.
A compound for inhibiting CYP1A (Cytochrome P450 subfamily 1A), including a compound represented by the following formula (1):
[Formula 1]
In Formula 1 above
X is any one of C, O or S,
A is either a hydroxy group or a straight-chain or branched alkoxy having 1-6 carbon atoms.
상기 화학식 1의 화합물은 아래의 화합물 1 내지 4중 어느 하나인 CYP1A 억제용 화합물:
[화합물 1]
[화합물 2]
[화합물 3]
[화합물 4]
According to claim 1,
The compound of Formula 1 is a compound for inhibiting CYP1A, which is any one of compounds 1 to 4 below:
[Compound 1]
[Compound 2]
[Compound 3]
[Compound 4]
A composition for inhibiting CYP1A (Cytochrome P450 subfamily 1A) comprising the compound of claim 1.
상기 CYP1A는 CYP1A1 및 CYP1A2 중 어느 하나 이상인 CYP1A 억제용 조성물.
4. The method of claim 3,
The CYP1A is a composition for inhibiting CYP1A at least one of CYP1A1 and CYP1A2.
상기 조성물은 약물상호작용 평가용인 CYP1A 억제용 조성물.
4. The method of claim 3,
The composition is a CYP1A inhibitory composition for drug interaction evaluation.
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| KR101496435B1 (en) | 2007-12-27 | 2015-03-03 | 에스케이바이오팜 주식회사 | Imidazole urea-based compound and cytochrome p450 activity inhibitor comprising thereof |
| WO2020223439A1 (en) * | 2019-04-30 | 2020-11-05 | Middle Tennessee State University | Aurones and methods of using aurones to treat tuberculosis |
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| KR101496435B1 (en) | 2007-12-27 | 2015-03-03 | 에스케이바이오팜 주식회사 | Imidazole urea-based compound and cytochrome p450 activity inhibitor comprising thereof |
| WO2020223439A1 (en) * | 2019-04-30 | 2020-11-05 | Middle Tennessee State University | Aurones and methods of using aurones to treat tuberculosis |
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| Title |
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| ACS Catal. 2018, 8, 4969-4978 (2018.04.12.)* * |
| Bioorganic & Medicinal Chemistry (2018), 26(1), 215-224 (2017.11.22.)* * |
| J Chin Chem Soc. 2020;67;623-637 (2019.08.23.)* * |
| Turk J Chem (2019) 43: 1445-1457 (2019.09.11.)* * |
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