KR102237728B1 - Map4k4 억제제를 유효성분으로 포함하는 항혈소판제용 조성물 - Google Patents
Map4k4 억제제를 유효성분으로 포함하는 항혈소판제용 조성물 Download PDFInfo
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Abstract
MAP4K4 억제제를 유효성분으로 포함하는 혈전 질환 예방 또는 치료용 약학적 조성물이 개시된다. MAP4K4 억제제가 단독 또는 다른 혈전증 치료제와 함께 병용투여되면 혈전 생성을 효과적으로 억제할 수 있다.
Description
본 발명은 MAP4K4 억제제를 유효성분으로 포함하는 혈전 질환 예방 또는 치료용 조성물에 관한 것이다.
혈전증(thrombosis)은 혈관 내에 혈전에 의해 발생하는 질환을 의미하고, 혈전이란 혈관 속에서 피가 굳어진 덩어리를 의미한다. 혈소판은 혈관 손상시 콜라겐(collagen), 트롬빈(thrombin), ADP 등 각종 물질의 자극에 의해 활성화되어 점착반응, 방출반응, 및 응집반응을 일으키며, 혈전증은 혈소판의 과잉 응집에 의해 매개되는 병리 현상이다.
기존 연구 결과에 따르면, 혈소판에 콜라겐, 트롬빈, 및 ADP 등의 자극이 가해지면, 혈소판 막에 존재하는 수용체에 의해서 혈소판이 자극을 인식하고, 혈소판 막 내에 존재하는 인지질 분해효소(phospholipase)가 활성화되어 포스파티딜이노시톨 4,5-비스포스페이트 (phophatidylinositol 4,5-bisphosphate; PIP2)가 분해되어, 그 결과로 디아실글리세롤(diacylglycerol; DG)과 이노시톨 1,4,5-트리스포스페이트 (inositol 1,4,5-trisphosphate; IP3)가 생성된다. 이 두 가지 생성물은 각각 혈소판의 활성에 주요한 물질로 작용한다. DG는 세포질에 성분인 아라키돈산(arachidonic acid)의 분해와 세포질로의 방출을 유도한다. 방출된 아라키돈산은 프로스타글란딘 G2/H2(prostaglandin G2/H2)로 전환되며, 이로부터 thromboxane A2 (TXA2)가 생성된다. Thromboxane A2은 혈액응고, 혈소판 응집 및 혈전형성 등에 주요하게 관여한다. 한편, IP3는 혈소판 내의 칼슘 저장 공간이 소포체의 IP3 수용체에 결합하여 소포체의 칼슘을 세포질로 동원시킨다. 동원된 칼슘은 혈소판 내에서 혈소판의 응집에 중요한 이차 전달자 (secondary messenger)로 기능 하는데, 칼슘은 여러 단백질의 인산화의 활성을 촉진시킨다. 그 결과로, 혈소판의 응집과 함께 혈소판 내의 과립(dense body, alpha-granule)에 저장되어있던 세로토닌(serotonin), ATP, ADP, 혈액응고 인자들, PDGF(platelet derived growth factor)의 분비가 유도된다. 이 중, PDGF는 동맥경화등의 중종(atheroma) 형성의 주요 원인이 되며, 세로토닌은 중추신경계의 신경전달물질, 심혈관계 및 위장간계의 평활근 작용, 혈소판 응집 촉진 작용 및 혈전형성의 조절자로서 다양한 생리작용을 도모한다.
혈전의 형성과 이를 매개하는 혈소판 응집 반응을 억제함으로써 혈전증을 예방, 치료하고자 하는 연구가 진행되고 있으나, 현재까지 개발된 의약품들은 그 부작용으로 인하여 이용에 한계가 있다. 따라서, 기존 혈전증 치료 용도의 의약품들과 병용처리를 하여 그 부작용을 낮출 수 있는 항혈전제를 개발하는 것이 시급한 실정이다.
일 구체예에 따르면 MAP4K4 단백질 발현을 억제함으로써 혈전 형성을 효과적으로 억제할 수 있는 혈전 질환 예방 또는 치료용 약학적 조성물을 제공한다.
일 양상은 MAP4K4 억제제를 유효성분으로 포함하는 혈전 질환 예방 또는 치료용 약학적 조성물을 제공한다. 상기 MAP4K4는 Mitogen-activated protein kinase kinase kinase kinase 4로서, 암 치료제의 표적으로 알려져 있으나 혈전 억제제의 표적으로는 알려진 바가 없다. 상기 MAP4K4는 서열번호 1의 아미노산 서열로 구성된 폴리펩타이드인 것일 수 있다. MAP4K4의 아미노산 서열은 하기 표 1에 기재되어 있다.
MAP4K4 / 서열번호 1 |
서열정보 |
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일 구체예에서, 상기 MAP4K4 억제제는 일일 투여량이 5 내지 60mg, 10 내지 60mg, 15 내지 60mg, 20 내지 60mg, 25 내지 60mg, 5 내지 55mg, 10 내지 55mg, 15 내지 55mg, 20 내지 55mg, 25 내지 55mg, 5 내지 50mg, 10 내지 50mg, 15 내지 50mg, 20 내지 50mg, 25 내지 50mg, 5 내지 45mg, 10 내지 45mg, 15 내지 45mg, 20 내지 45mg, 25 내지 45mg, 5 내지 40mg, 10 내지 40mg, 15 내지 40mg, 20 내지 40mg, 25 내지 40mg, 5 내지 35mg, 10 내지 35mg, 15 내지 35mg, 20 내지 35mg, 25 내지 35mg, 5 내지 30mg, 10 내지 30mg, 15 내지 30mg, 20 내지 30mg, 또는 25 내지 30mg일 수 있다. 본 발명자는 MAP4K4 억제제인 GNE495가 아스피린의 권장 투여량보다 1/5만큼을 사용하더라도 혈전 억제 효과가 더 우수하면서도 그 범위에서 혈소판에 대한 독성이 없음을 확인하였다.
일 구체예에서, 상기 MAP4K4 억제제는 8-아미노-N-[1-(사이클로프로필카보닐)-3-아제티디닐]-2-(3-플루오로페닐)-1,7-나프틸리딘-5-카복사마이드(8-amino-N-[1-(cyclopropylcarbonyl)-3-azetidinyl]-2-(3-fluorophenyl)-1,7-naphthyridine-5-carboxamide, 이하 GNE-495로 지칭할 수 있다)일 수 있으며, 구조는 하기 화학식 1과 같다.
상기 화학식 1의 물질은 GNE-495로도 알려져 있으며, Cas 번호는 1449277-10-4이다. 본 발명자는 혈소판에 MAP4K4가 존재함을 확인하였으며, MAP4K4 억제제인 GNE-495를 단독 투여하는 경우 콜라겐 또는 트롬빈에 의한 혈전 형성을 억제하고, 혈소판 응집을 유도하는 TXA2의 생성 및 세로토닌 방출을 억제함을 확인하였으므로 8-아미노-N-[1-(사이클로프로필카보닐)-3-아제티디닐]-2-(3-플루오로페닐)-1,7-나프틸리딘-5-카복사마이드를 혈전 질환의 예방 또는 치료에 유용하게 사용할 수 있다.
일 구체예에서, 상기 조성물은 아스피린을 더 포함할 수 있다. 본 발명자는 아스피린과 GNE-495를 병용투여하면 혈전 형성을 효과적으로 억제할 수 있음을 확인하였다. 상기 아스피린(aspirin)은 아세틸 살리실산(acetylsalicylic acid)로서 항혈전 효과를 가지지만 고용량으로 투여시 뇌출혈 등 부작용이 크게 증가하는 것으로 알려져 있다.
일 구체예에서, 상기 아스피린과 상기 MAP4K4 억제제의 성분비는 몰수를 기준으로 4:1 내지 6:1, 4.5:1 내지 5.5:1, 또는 5:1일 수 있다. 본 발명자는 MAP4K4 억제제를 아스피린과 병용투여하는 경우 혈전 억제 효과가 상승함을 확인하였으며, 특히 아스피린과 MAP4K4 억제제인 GNE-495를 농도를 기준으로 5:1의 비율로 투여하는 경우 가장 혈전 억제 효과가 우수함을 확인하였다. 일반적으로 심혈관 예방 및 치료에 이용되는 아스피린의 농도는 100μM이며, 이는 아스피린의 농도를 100μM로 투여하는 경우 혈소판 응집 마커인 TXA2의 생성을 가장 효과적으로 억제하기 때문이다(aspirin은 TXA2의 생성을 선택적으로 억제하는 혈전 저해제). 이를 기준으로 GNE-495를 병용 투여한 결과, GNE-495 농도 20 uM에서 혈소판 응집에 있어서 가장 유의한 효과를 나타내었다.
일 구체예에서, 상기 조성물은 디피리다몰(Dipyridamole), 또는 아스피린 및 디피리다몰을 더 포함할 수 있다. 상기 디피리다몰은 상표명 퍼산틴(persantine)으로도 알려져 있으며 혈관 응고를 억제하는 효과가 알려져 있다.
상기 MAP4K4 억제제 및 상기 디피리다몰을 포함하는 경우 성분비는 몰수를 기준으로 1.5:1 내지 0.5:1, 또는 1:1일 수 있다.
상기 아스피린, 상기 MAP4K4 억제제, 및 상기 디피리다몰을 포함하는 경우 성분비는 몰수를 기준으로 4:1:1 내지 6:1:1, 4.5:1:1 내지 5.5:1:1, 5:1:1일 수 있다. 아스피린과 디피리다몰의 혼합제제는 혈전증 치료제로서 처방되고 있으며, 이에 MAPK4 억제제인 GNE-495를 더 포함하여 병용 투여하면 기존 아스피린 및 디피리다몰의 병용제제보다 혈전 억제 효과가 상승할 수 있다. 특히 아스피린은 최대 100-300 mg/day의 투여가 가능하다고 알려져 있으나, 저용량(100 mg/day)과 고용량(300 mg/day)의 항혈전 효과 차이가 크지 않으면서 뇌출혈 등의 부작용 위험은 용량에 비례하여 증가하므로 75 내지 100 mg/day의 투여량이 권장되고 있다(이철환, 항혈소판제의 심혈관질환 예방효과). 그러나, 본 발명자는 저용량의 아스피린(100 μM)과 GNE-495를 병용투여하는 경우 각각의 투여량을 증가시키지 않아 부작용을 억제하면서도 아스피린의 고용량을 투여한 것보다 더 높은 항혈전 효과를 달성할 수 있음을 확인하였다.
일 구체예에서, 상기 혈전 질환은 혈전증, 동맥 혈전증, 정맥 혈전증, 간문맥 혈전증, 관상 및 뇌동맥 혈전증, 말초혈관 또는 심부정맥 혈전증, 폐동맥 색전증, 동맥 색전증, 뇌 색전증, 신장 색전증, 및 혈전 색전증으로 이루어진 군으로부터 선택된 것일 수 있다.
혈전증은 심장성, 동맥성, 정맥성, 수술 등의 원인에 의해 발병할 수 있으나, 공통적으로 혈소판의 활성이 근본 원인이다. 따라서 혈전증을 예방 및 치료하기 위해서는 혈소판 자체의 응집 활성을 억제하는 것이 효과적이며, 혈전 억제제는 혈소판의 활성기전을 특이적으로 억제하는 약물들이다. 예를 들면 아스피린은 Cox-1 효소 활성을 억제하며, 디피리다몰은 PDE 효소활성을 억제하며, 클로피도그렐(clopidogrel)은 P2Y12 receptor를 억제한다. 본 발명의 조성물은 MAP4K4 단백질을 억제함으로서 혈소판 활성을 억제하므로 기존 약물과 활성기전의 억제 원리에서 차이가 있다.
상기 약학적 조성물은 약학적으로 허용가능한 염을 포함하는 것을 의도하는 것으로 이해될 수 있다. 이러한 약학적으로 허용가능한 염은 통상적으로 이용되는 염의 제조방법에 의해서 제조될 수 있다. 상기 '약학적으로 허용가능한 염'은 무기 또는 유기 염기 및 무기 또는 유기 산을 포함하는 약학적으로 허용가능한 비독성 염기 또는 산으로부터 제조되는 염을 말한다. 무기 염기로부터 유도되는 염은 알루미늄, 암모늄, 칼슘, 구리, 제이철, 제일철, 리튬, 마그네슘, 망간 염, 망간, 칼륨, 나트륨, 아연 등을 포함한다. 특히 암모늄, 칼슘, 마그네슘, 칼륨 또는 나트륨 염이 바람직하다. 고형의 염은 하나 이상의 결정 구조로 존재할 수 있고, 또한 수화물 형태로 존재할 수 있다. 약학적으로 허용되는 비독성 유기 염기로부터 유도된 염은 일급, 이급 또는 삼급 아민, 천연적으로 치환된 아민을 포함하는 치환된 아민, 아민 환, 또는 아르기닌, 베타인, 카페인, 콜린, N,N'-디벤질에틸렌디아민, 디에틸아민, 2-디에틸아미노에탄올, 2-디메틸아미노에탄올, 에탄올아민, 에틸렌디아민, N-에틸몰포린, N-에틸피페리딘, 글루카민, 글루코사민, 히스티딘, 하이드라바민, 이소프로필아민, 라이신, 메틸글루카민, 포폴린, 피페라진, 피페리딘, 폴리아민 수지, 프로카인, 퓨린, 테오브로민, 트리에틸아민, 트리메틸아민, 트리프로필아민, 트로메타민 등과 같은 염기성 이온 교환 수지를 포함한다. 본 발명의 화합물이 염기성인 경우, 염은 무기 및 유기 산을 포함하는 약학적으로 허용되는 비독성 산으로부터 제조될 수 있다. 상기 산은 아세트산, 벤젠술폰산, 벤조산, 캄포르술폰산, 시트르산, 에탄술폰산, 퓨마르산, 글루콘산, 글루탐산, 하이드로브롬산, 염산, 이세티온산, 락트산, 말레산, 말산, 만델산, 메탄술폰산, 뮤크산, 질산, 파모산, 판토텐산, 인산, 숙신산, 황산, 타르타르산, p-톨루엔술폰산 등을 포함한다.
상기 약학적 조성물은 유효성분 외에 약제학적으로 적합하고 생리학적으로 허용되는 보조제를 사용하여 제조할 수 있으며, 상기 보조제로는 부형제, 감미제, 결합제, 피복제, 팽창제, 윤활제, 또는 향미제 등을 사용할 수 있다.
상기 약학적 조성물은 투여를 위해 유효성분 외에 추가로 약제학적으로 허용 가능한 담체를 1종 이상 포함하여 의약 조성물로 바람직하게 제제화할 수 있다.
상기 약학적 조성물의 제제 형태는 과립제, 산제, 정제, 캡슐제, 좌제, 액제, 시럽, 현탁액, 주사제, 또는 점적제 등이 될 수 있다. 예를 들어, 정제 또는 캡슐제의 형태로의 제제화를 위해, 유효 성분은 에탄올, 글리세롤, 물 등과 같은 경구, 무독성의 약제학적으로 허용 가능한 불활성 담체와 결합될 수 있다. 또한, 원하거나 필요한 경우, 적합한 결합제, 윤활제, 붕해제 및 발색제 또한 혼합물로 포함될 수 있다. 적합한 결합제는 이에 제한되는 것은 아니나, 녹말, 젤라틴, 글루코스 또는 베타-락토오스와 같은 천연당, 옥수수 감미제, 아카시아, 트래커캔스 또는 소듐올레이트와 같은 천연 및 합성 검, 소듐 스테아레이트, 마그네슘 스테아레이트, 소듐 벤조에이트, 소듐 아세테이트, 소듐 클로라이드 등을 포함한다. 붕해제는 이에 제한되는 것은 아니나, 녹말, 메틸 셀룰로스, 아가, 벤토니트, 잔탄 검 등을 포함한다. 액상 용액으로 제제화되는 조성물에 있어서 허용 가능한 약제학적 담체로는, 멸균 및 생체에 적합한 것으로서, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사용액, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 더 나아가 해당분야의 적절한 방법으로 Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제제화 할 수 있다.
상기 약학적 조성물은 경구 투여 또는 비경구투여(예를 들면 정맥, 피하, 복강에 적용)할 수 있으며, 투여량은 환자의 상태 및 체중, 질병의 정도, 투여 경로 및 시간에 따라 다를 수 있으며, 통상기술자에 의해 적절하게 선택될 수 있다. 상기 약학적 조성물의 일일 투여량은 바람직하게는 1ng/kg 내지 100mg/kg이며, 필요에 따라 일일 1회 내지 수회로 나누어 투여할 수 있다.
다른 양상은 MAP4K4 억제제를 유효성분으로 포함하는 혈전 질환 예방 또는 개선용 건강기능식품 조성물을 제공한다.
상기 MAP4K4 억제제는 8-아미노-N-[1-(사이클로프로필카보닐)-3-아제티디닐]-2-(3-플루오로페닐)-1,7-나프틸리딘-5-카복사마이드(8-amino-N-[1-(cyclopropylcarbonyl)-3-azetidinyl]-2-(3-fluorophenyl)-1,7-naphthyridine-5-carboxamide일 수 있으며, MAPK4K 억제제 및 8-아미노-N-[1-(사이클로프로필카보닐)-3-아제티디닐]-2-(3-플루오로페닐)-1,7-나프틸리딘-5-카복사마이드(8-amino-N-[1-(cyclopropylcarbonyl)-3-azetidinyl]-2-(3-fluorophenyl)-1,7-naphthyridine-5-carboxamide에 대한 사항은 앞서 설명한 내용과 동일하다.
상기 건강기능식품은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 천연 과일 주스 및 합성 과일 주스 등의 과일 주스 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 또한, 건강기능식품은 육류, 소세지, 빵, 초콜릿, 캔디류, 스넥류, 과자류, 피자, 라면, 껌류, 아이스크림류, 스프, 음료수, 차, 기능수, 드링크제, 알코올 및 비타민 복합제 중 어느 하나의 형태일 수 있다.
상기 건강기능식품은 식품첨가물을 추가로 포함할 수 있으며, "식품첨가물"로서의 적합여부는 다른 규정이 없는 한 식품의약품안정청에 승인된 식품첨가물공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다. 상기 "식품첨가물공전"에 수재된 품목으로 예를 들어, 케톤류, 글리신, 구연산 칼륨, 니코틴산, 계피산 등의 화학적 합성품, 감색소, 감초추출물, 결정셀룰로오스, 고랭색소, 구아검 등의 천연첨가물, L-글루타민산나트륨제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류 등을 들 수 있다. 건강기능식품을 제조하는 과정에서 식품에 첨가되는 본 발명에 따른 MAP4K4 억제제는 필요에 따라 그 함량을 적절히 가감할 수 있으며, 바람직하게는 식품 100 중량%에 대해 0.001 중량% 내지 5 중량% 포함되도록 첨가하는 것이 바람직하다.
일 구체예에 따른 혈전 질환 예방 또는 치료용 약학적 조성물을 이용하면, MAP4K 억제제를 단독 또는 아스피린 및 디피리다몰 중 하나 이상과 병용 투여함으로써 각 물질을 고용량으로 단독 투여하는 경우보다 혈전 형성을 효과적으로 억제할 수 있으며, 각각의 물질을 더 적은 용량을 투여하므로 부작용을 감소시킬 수 있다.
도 1은 일 실시예에 따른 사람의 혈소판에서 MAP4K4 단백질의 존재를 확인한 결과이다.
도 2의 A는 콜라겐(3 μg/mL)에 의해 유도된 혈소판 응집에 대한 GNE-495의 응집 저해 효과를 나타낸 것이다. 도 2의 B는 콜라겐 (3 μg/mL)에 의해 유도된 혈소판 응집에 대한 GNE-495, aspirin, dipyridamole의 병용 투여시 응집 저해 효과를 나타낸 것이다. 도 2의 C는 아스피린의 100 μM 및 500 μM 투여시 혈소판 응집 저해 효과를 나타낸 것이다.
도 3은 일 실시예에 따른 콜라겐 (3 μg/mL) 유도 TXB2 생성에 대한 GNE-495의 TXB2 생성 저해 효과를 확인한 결과이다.
도 4는 일 실시예에 따른 콜라겐(3 μg/mL)에 의해 유도된 세로토닌 방출에 대한 GNE-495의 방출 저해 효과를 확인한 결과이다.
도 5는 thrombin (0.2 U/mL) 유도 혈병 수축에 대한 GNE-495의 혈병 수축 억제 효과를 확인한 결과이다.
도 6은 GNE-495의 혈소판에 대한 독성을 확인한 결과이다.
도 7은 GNE-495 및 아스피린의 병용처리시 상승 효과를 분석한 결과이다. 도 7의 G+A는 GNE-495 20 μM 및 아스피린 100 μM을 처리한 것을 의미한다.
도 2의 A는 콜라겐(3 μg/mL)에 의해 유도된 혈소판 응집에 대한 GNE-495의 응집 저해 효과를 나타낸 것이다. 도 2의 B는 콜라겐 (3 μg/mL)에 의해 유도된 혈소판 응집에 대한 GNE-495, aspirin, dipyridamole의 병용 투여시 응집 저해 효과를 나타낸 것이다. 도 2의 C는 아스피린의 100 μM 및 500 μM 투여시 혈소판 응집 저해 효과를 나타낸 것이다.
도 3은 일 실시예에 따른 콜라겐 (3 μg/mL) 유도 TXB2 생성에 대한 GNE-495의 TXB2 생성 저해 효과를 확인한 결과이다.
도 4는 일 실시예에 따른 콜라겐(3 μg/mL)에 의해 유도된 세로토닌 방출에 대한 GNE-495의 방출 저해 효과를 확인한 결과이다.
도 5는 thrombin (0.2 U/mL) 유도 혈병 수축에 대한 GNE-495의 혈병 수축 억제 효과를 확인한 결과이다.
도 6은 GNE-495의 혈소판에 대한 독성을 확인한 결과이다.
도 7은 GNE-495 및 아스피린의 병용처리시 상승 효과를 분석한 결과이다. 도 7의 G+A는 GNE-495 20 μM 및 아스피린 100 μM을 처리한 것을 의미한다.
이하 하나 이상의 구체예를 실시예를 통해 보다 상세하게 설명한다. 그러나, 이들 실시예는 하나 이상의 구체예를 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.
실시예 1: 혈소판 내 MAP4K4 단백질의 존재 확인
1-1. 혈소판 준비
본 실험에 사용한 혈소판은 인간의 혈소판으로서, 건강한 성인으로부터 자유 헌혈의지에 의해 채혈된 혈액제제 중 대한적십자사 혈액원에서 연구용으로 반출된 농축혈소판이다. Auto activation을 피하기 위해 실험 전 보관은 20~24℃를 유지하여 500 rpm으로 교반하며 보관하였다.
1-2. 혈소판 내 MAP4K4 단백질의 존재 확인
Human platelet-rich plasma(PRP)를 washing buffer를 이용하여 2회 세척 후, 혈소판을 suspension buffer를 이용하여 혈소판 부유액 (5 × 108/mL)을 만들어 실험을 진행하였다. 아무런 자극을 받지 않은 혈소판 (108/mL)을 단백질 분해효소 저해제가 포함된 RIPA lysis buffer로 세포를 용해한 후 13,000 rpm에서 10분간 원심분리하였다. 상청액을 새 튜브에 옮겨 단백질 농도를 bicinchoninic acid/copper sulfate 방법으로 측정하고 정량한 단백질을 SDS-PAGE로 분리하였다. 분리한 단백질은 PVDF 막으로 옮겨 blocking 용액에 넣어서 1 시간 동안 반응 시킨 후 TBST로 세척하였다. 이어서, PVDF 막에 MAP4K4 단백질에 대한 1차 항체가 포함된 용액으로 밤새 4℃에서 반응시킨 후 TBST로 세척하고, HRP가 결합된 2차 항체 반응을 상온에서 1시간 수행하였다. MAP4K4 단백질 band는 chemiluminascent 기질 반응을 LAS-4000 (Fujifilm, 일본)을 이용하여 확인하였다.
도 1에 나타낸 바와 같이, 사람의 혈소판에서 MAP4K4 단백질이 존재하는 것을 확인하였다.
실시예 2: GNE-495의 콜라겐 유도에 의한 혈소판 응집 억제 효과 확인
human platelet-rich plasma (PRP)를 washing buffer를 이용하여 2회 세척 후, 혈소판을 suspension buffer를 이용하여 혈소판 부유액 (5 × 108/mL)을 만들어 실험을 진행하였다. 혈소판 (108/mL)을 콜라겐 (3 ㎍/mL)으로 5 분간 자극시켰으며, aggregometer (Chrono-Log Co.)를 이용하여 응집을 관찰하였다. 응집반응의 정도는 light transmission을 이용하여 monitoring 하였으며, 콜라겐 단독 사용을 기준으로 하여 GNE-495의 저해 효과를 관찰하였다.
도 2의 A에 나타낸 바와 같이, 사람혈소판을 콜라겐 (3 ㎍/mL) (53.3 ± 6.5%)으로 응집을 유도하였다. GNE-495 (20 μM)는 콜라겐 (3 ㎍/mL)으로 유도된 혈소판 응집을 24.5 ± 11.4%까지 억제하였으며, 이는 콜라겐에 의해 유도된 혈소판 응집을 효과적으로 억제함을 나타낸다.
뿐만 아니라, 도 2의 B 및 C에 나타낸 바와 같이 GNE-495는 저용량의 아스피린(100 μM)과 dipyridamole과 병용처리 하였을 때 아스피린을 단독으로 고용량(500 μM)으로 투여한 경우 달성할 수 있는 혈소판 응집 억제 효과보다 뛰어남을 확인하였으므로 보다 혈소판 응집 억제 효과의 상승 작용 및 부작용 감소 효과를 확인할 수 있었다.
실시예 3: GNE-495의 TXA
2
생성 억제 효과 확인
혈소판 (108/mL)을 콜라겐(3 μg/mL)으로 5 분간 자극시킨 후 indomethacin (0.2 mM)을 첨가하여 반응을 정지 시켰다. 반응이 정지된 샘플을 5,000 rpm으로 10분간 원심분리 후 상청을 새 튜브에 옮겨 500배 희석 하여 TXB2 (TXA2의 안정형 상태)를 TXB2 EIA kit를 이용하여 제조사에서 제시한 방법에 따라 함량을 분석하였다.
Thromboxane A2 (TXA2)는 혈소판 자극제에 의해서 활성화된 혈소판의 세포막의 인지질이 대사되어 생성된다. 생성된 TXA2는 주변의 혈소판을 자극하여 혈소판의 응집을 강화시키며, 짧은 시간 후 비활성 대사물질인 Thromboxane B2 (TXB2)로 전환된다. 도 3에 나타낸 바와 같이, 대조군은 콜라겐 (3 μg/mL)의 자극에 의해 TXB2의 생성량이 34.5 ± 4.5 ng/mL에서 805.2 ± 49.1 ng/mL까지 증가한 반면, GNE-495 (20 μM)를 처리한 군은 TXB2의 생성량이 254.5 ± 4.8 ng/mL으로 대조군과 비교하면 TXB2 생성량이 절반 이하로 억제됨을 확인하였다. TXA2 생성 저해 약물인 아스피린 100 μM만을 처리한 군에서는 TXB2의 생성량이 345.5 ± 11.5 ng/mL까지 억제되었으며, 아스피린과 GNE-495을 병용처리 하였을 때 추가적인 억제효과를 나타내었다.
실시예 4: GNE-495의 혈소판 활성물질인 세로토닌 방출 억제 효과 확인
혈소판 (108/mL)을 콜라겐 (3 μg/mL)으로 5 분간 자극시킨 후 indomethacin (0.2 mM)/EDTA (5 mM)을 첨가하여 반응을 정지 시켰다. 반응이 정지된 샘플을 5,000 rpm으로 10분간 원심분리 후 상청을 새 튜브에 옮겨 세로토닌 EIA kit를 이용하여 제조사에서 제시한 방법에 따라 함량을 분석하였다.
세로토닌은 혈소판의 소포체 내에 저장 상태로 존재하며, 혈소판이 활성화되면 혈소판 외부로 방출되어 혈소판의 응집을 강화시킨다. 도 4에 나타낸 바와 같이, 혈소판은 콜라겐(3 μg/mL)의 자극에 의해 세로토닌을 40.2 ± 16.4 nM에서 344.1 ± 30.8 nM까지 방출 하였으며, GNE-495 (20 μM)에 의해 193.5 ± 24.1 nM까지 효과적으로 방출을 억제 하였다.
실시예 5: GNE-495의 혈병 수축에 대한 억제 효과 확인
human platelet-rich plasma (PRP)를 3,000 rpm, 10분 동안 원심분리하여 human platelet-poor plasma (PPP)를 제조하였다. 침전된 혈소판을 5 × 108/mL으로 정량하여 PRP에 넣어 1 × 108/mL PRP를 제조한 후 튜브당 250μL씩 새 튜브로 옮겼다. 각 튜브당 thrombin(0.2 U/mL)를 넣고 37℃에서 2시간 동안 반응 시켰다. 혈전 형성 (혈병 수축) 반응은 카메라로 관찰 하였다.
도 5에 나타낸 바와 같이, thrombin (0.2 U/mL)을 이용하여 PRP (1 × 108/mL)에서 혈병 수축을 유도하였다. thrombin (0.2 U/mL)에 의해 혈병 수축이 나타 났으며, GNE-495는 혈병 수축을 농도, 시간 의존적으로 억제함을 확인하였다.
실시예 6: GNE-495의 혈소판에 대한 독성 평가
GNE-495의 용량에 따른 혈소판에 대한 독성을 확인하기 위해 LDH(Lactate Dehydrogenase) 수치 검사를 실시하였다. LDH는 세포가 손상되거나 파괴될 때 유출되기 때문에 세포 손상의 지표로서 사용된다.
도 6에 따르면 혈소판을 용혈시키는 Triton-X 100을 대조군으로 사용하고 GNE-495의 투여용량에 따른 LDH 수치를 확인한 결과, GNE 495는 20 μM 투여시에도 혈소판에 대한 독성을 나타내지 않음을 확인하였다.
실시예 7: GNE-495와 아스피린의 병용투여시 상승효과 분석
도 7은 혈소판 응집실험에서 GNE-495 20μM 및 아스피린 100μM을 병용하여 처리한 결과를 분석한 것이다. CI가 1보다 크면 효과를 감소시키는 길항제 역할을 하는 것이며, CI가 1과 같으면 용량 의존적으로 효과가 증가하는 것이며, CI가 1보다 적은 수일 때 시너지 효과를 나타내는 것으로 평가될 수 있다. 분석 결과, GNE-495 20μM 및 아스피린 100μM을 병용처리하면 유의미하게 상승효과가 있는 것으로 확인되었다.
<110> Dongguk University Gyeongju Campus Industry-Academy Cooperation Foundation
<120> Composition For The Prevention Or Treatment Of Thrombosis Disease
Comprising 5-(4-Chlorophenyl)-[3,3 '] Bipyridinyl-6,6'-Diamine
Dihydrochloride As An Active Ingredient
<130> PN190311
<160> 1
<170> KoPatentIn 3.0
<210> 1
<211> 1165
<212> PRT
<213> Artificial Sequence
<220>
<223> MAP4K4 amino acid sequence
<400> 1
Met Ala Asn Asp Ser Pro Ala Lys Ser Leu Val Asp Ile Asp Leu Ser
1 5 10 15
Ser Leu Arg Asp Pro Ala Gly Ile Phe Glu Leu Val Glu Val Val Gly
20 25 30
Asn Gly Thr Tyr Gly Gln Val Tyr Lys Gly Arg His Val Lys Thr Gly
35 40 45
Gln Leu Ala Ala Ile Lys Val Met Asp Val Thr Glu Asp Glu Glu Glu
50 55 60
Glu Ile Lys Leu Glu Ile Asn Met Leu Lys Lys Tyr Ser His His Arg
65 70 75 80
Asn Ile Ala Thr Tyr Tyr Gly Ala Phe Ile Lys Lys Ser Pro Pro Gly
85 90 95
His Asp Asp Gln Leu Trp Leu Val Met Glu Phe Cys Gly Ala Gly Ser
100 105 110
Ile Thr Asp Leu Val Lys Asn Thr Lys Gly Asn Thr Leu Lys Glu Asp
115 120 125
Trp Ile Ala Tyr Ile Ser Arg Glu Ile Leu Arg Gly Leu Ala His Leu
130 135 140
His Ile His His Val Ile His Arg Asp Ile Lys Gly Gln Asn Val Leu
145 150 155 160
Leu Thr Glu Asn Ala Glu Val Lys Leu Val Asp Phe Gly Val Ser Ala
165 170 175
Gln Leu Asp Arg Thr Val Gly Arg Arg Asn Thr Phe Ile Gly Thr Pro
180 185 190
Tyr Trp Met Ala Pro Glu Val Ile Ala Cys Asp Glu Asn Pro Asp Ala
195 200 205
Thr Tyr Asp Tyr Arg Ser Asp Leu Trp Ser Cys Gly Ile Thr Ala Ile
210 215 220
Glu Met Ala Glu Gly Ala Pro Pro Leu Cys Asp Met His Pro Met Arg
225 230 235 240
Ala Leu Phe Leu Ile Pro Arg Asn Pro Pro Pro Arg Leu Lys Ser Lys
245 250 255
Lys Trp Ser Lys Lys Phe Phe Ser Phe Ile Glu Gly Cys Leu Val Lys
260 265 270
Asn Tyr Met Gln Arg Pro Ser Thr Glu Gln Leu Leu Lys His Pro Phe
275 280 285
Ile Arg Asp Gln Pro Asn Glu Arg Gln Val Arg Ile Gln Leu Lys Asp
290 295 300
His Ile Asp Arg Thr Arg Lys Lys Arg Gly Glu Lys Asp Glu Thr Glu
305 310 315 320
Tyr Glu Tyr Ser Gly Ser Glu Glu Glu Glu Glu Glu Val Pro Glu Gln
325 330 335
Glu Gly Glu Pro Ser Ser Ile Val Asn Val Pro Gly Glu Ser Thr Leu
340 345 350
Arg Arg Asp Phe Leu Arg Leu Gln Gln Glu Asn Lys Glu Arg Ser Glu
355 360 365
Ala Leu Arg Arg Gln Gln Leu Leu Gln Glu Gln Gln Leu Arg Glu Gln
370 375 380
Glu Glu Tyr Lys Arg Gln Leu Leu Ala Glu Arg Gln Lys Arg Ile Glu
385 390 395 400
Gln Gln Lys Glu Gln Arg Arg Arg Leu Glu Glu Gln Gln Arg Arg Glu
405 410 415
Arg Glu Ala Arg Arg Gln Gln Glu Arg Glu Gln Arg Arg Arg Glu Gln
420 425 430
Glu Glu Lys Arg Arg Leu Glu Glu Leu Glu Arg Arg Arg Lys Glu Glu
435 440 445
Glu Glu Arg Arg Arg Ala Glu Glu Glu Lys Arg Arg Val Glu Arg Glu
450 455 460
Gln Glu Tyr Ile Arg Arg Gln Leu Glu Glu Glu Gln Arg His Leu Glu
465 470 475 480
Val Leu Gln Gln Gln Leu Leu Gln Glu Gln Ala Met Leu Leu His Asp
485 490 495
His Arg Arg Pro His Pro Gln His Ser Gln Gln Pro Pro Pro Pro Gln
500 505 510
Gln Glu Arg Ser Lys Pro Ser Phe His Ala Pro Glu Pro Lys Ala His
515 520 525
Tyr Glu Pro Ala Asp Arg Ala Arg Glu Val Pro Val Arg Thr Thr Ser
530 535 540
Arg Ser Pro Val Leu Ser Arg Arg Asp Ser Pro Leu Gln Gly Ser Gly
545 550 555 560
Gln Gln Asn Ser Gln Ala Gly Gln Arg Asn Ser Thr Ser Ile Glu Pro
565 570 575
Arg Leu Leu Trp Glu Arg Val Glu Lys Leu Val Pro Arg Pro Gly Ser
580 585 590
Gly Ser Ser Ser Gly Ser Ser Asn Ser Gly Ser Gln Pro Gly Ser His
595 600 605
Pro Gly Ser Gln Ser Gly Ser Gly Glu Arg Phe Arg Val Arg Ser Ser
610 615 620
Ser Lys Ser Glu Gly Ser Pro Ser Gln Arg Leu Glu Asn Ala Val Lys
625 630 635 640
Lys Pro Glu Asp Lys Lys Glu Val Phe Arg Pro Leu Lys Pro Ala Gly
645 650 655
Glu Val Asp Leu Thr Ala Leu Ala Lys Glu Leu Arg Ala Val Glu Asp
660 665 670
Val Arg Pro Pro His Lys Val Thr Asp Tyr Ser Ser Ser Ser Glu Glu
675 680 685
Ser Gly Thr Thr Asp Glu Glu Asp Asp Asp Val Glu Gln Glu Gly Ala
690 695 700
Asp Glu Ser Thr Ser Gly Pro Glu Asp Thr Arg Ala Ala Ser Ser Leu
705 710 715 720
Asn Leu Ser Asn Gly Glu Thr Glu Ser Val Lys Thr Met Ile Val His
725 730 735
Asp Asp Val Glu Ser Glu Pro Ala Met Thr Pro Ser Lys Glu Gly Thr
740 745 750
Leu Ile Val Arg Gln Thr Gln Ser Ala Ser Ser Thr Leu Gln Lys His
755 760 765
Lys Ser Ser Ser Ser Phe Thr Pro Phe Ile Asp Pro Arg Leu Leu Gln
770 775 780
Ile Ser Pro Ser Ser Gly Thr Thr Val Thr Ser Val Val Gly Phe Ser
785 790 795 800
Cys Asp Gly Met Arg Pro Glu Ala Ile Arg Gln Asp Pro Thr Arg Lys
805 810 815
Gly Ser Val Val Asn Val Asn Pro Thr Asn Thr Arg Pro Gln Ser Asp
820 825 830
Thr Pro Glu Ile Arg Lys Tyr Lys Lys Arg Phe Asn Ser Glu Ile Leu
835 840 845
Cys Ala Ala Leu Trp Gly Val Asn Leu Leu Val Gly Thr Glu Ser Gly
850 855 860
Leu Met Leu Leu Asp Arg Ser Gly Gln Gly Lys Val Tyr Pro Leu Ile
865 870 875 880
Asn Arg Arg Arg Phe Gln Gln Met Asp Val Leu Glu Gly Leu Asn Val
885 890 895
Leu Val Thr Ile Ser Gly Lys Lys Asp Lys Leu Arg Val Tyr Tyr Leu
900 905 910
Ser Trp Leu Arg Asn Lys Ile Leu His Asn Asp Pro Glu Val Glu Lys
915 920 925
Lys Gln Gly Trp Thr Thr Val Gly Asp Leu Glu Gly Cys Val His Tyr
930 935 940
Lys Val Val Lys Tyr Glu Arg Ile Lys Phe Leu Val Ile Ala Leu Lys
945 950 955 960
Ser Ser Val Glu Val Tyr Ala Trp Ala Pro Lys Pro Tyr His Lys Phe
965 970 975
Met Ala Phe Lys Ser Phe Gly Glu Leu Val His Lys Pro Leu Leu Val
980 985 990
Asp Leu Thr Val Glu Glu Gly Gln Arg Leu Lys Val Ile Tyr Gly Ser
995 1000 1005
Cys Ala Gly Phe His Ala Val Asp Val Asp Ser Gly Ser Val Tyr Asp
1010 1015 1020
Ile Tyr Leu Pro Thr His Val Arg Lys Asn Pro His Ser Met Ile Gln
1025 1030 1035 1040
Cys Ser Ile Lys Pro His Ala Ile Ile Ile Leu Pro Asn Thr Asp Gly
1045 1050 1055
Met Glu Leu Leu Val Cys Tyr Glu Asp Glu Gly Val Tyr Val Asn Thr
1060 1065 1070
Tyr Gly Arg Ile Thr Lys Asp Val Val Leu Gln Trp Gly Glu Met Pro
1075 1080 1085
Thr Ser Val Ala Tyr Ile Arg Ser Asn Gln Thr Met Gly Trp Gly Glu
1090 1095 1100
Lys Ala Ile Glu Ile Arg Ser Val Glu Thr Gly His Leu Asp Gly Val
1105 1110 1115 1120
Phe Met His Lys Arg Ala Gln Arg Leu Lys Phe Leu Cys Glu Arg Asn
1125 1130 1135
Asp Lys Val Phe Phe Ala Ser Val Arg Ser Gly Gly Ser Ser Gln Val
1140 1145 1150
Tyr Phe Met Thr Leu Gly Arg Thr Ser Leu Leu Ser Trp
1155 1160 1165
Claims (10)
- 8-아미노-N-[1-(사이클로프로필카보닐)-3-아제티디닐]-2-(3-플루오로페닐)-1,7-나프틸리딘-5-카복사마이드를 유효성분으로 포함하고,
혈전증, 동맥 혈전증, 정맥 혈전증, 간문맥 혈전증, 관상 및 뇌동맥 혈전증, 말초혈관 또는 심부정맥 혈전증, 폐동맥 색전증, 동맥 색전증, 뇌 색전증, 신장 색전증, 및 혈전 색전증으로 이루어진 군으로부터 선택되는 질환을 예방 또는 치료하기 위한 약학적 조성물.
- 제 1 항에 있어서,
상기 8-아미노-N-[1-(사이클로프로필카보닐)-3-아제티디닐]-2-(3-플루오로페닐)-1,7-나프틸리딘-5-카복사마이드는 일일 투여량이 25 내지 40mg인,
혈전 질환 예방 또는 치료용 약학적 조성물.
- 삭제
- 제 1 항에 있어서,
상기 조성물은 아스피린을 더 포함하는,
혈전 질환 예방 또는 치료용 약학적 조성물. - 제 4 항에 있어서,
상기 아스피린과 상기 8-아미노-N-[1-(사이클로프로필카보닐)-3-아제티디닐]-2-(3-플루오로페닐)-1,7-나프틸리딘-5-카복사마이드의 성분비는 몰수를 기준으로 4:1 내지 6:1인,
혈전 질환 예방 또는 치료용 약학적 조성물. - 제 4 항에 있어서,
상기 조성물은 디피리다몰(Dipyridamole)을 더 포함하는,
혈전 질환 예방 또는 치료용 약학적 조성물. - 제 6 항에 있어서,
상기 아스피린, 상기 8-아미노-N-[1-(사이클로프로필카보닐)-3-아제티디닐]-2-(3-플루오로페닐)-1,7-나프틸리딘-5-카복사마이드, 및 상기 디피리다몰의 성분비는 몰수를 기준으로 4:1:1 내지 6:1:1인,
혈전 질환 예방 또는 치료용 약학적 조성물.
- 삭제
- 삭제
- 8-아미노-N-[1-(사이클로프로필카보닐)-3-아제티디닐]-2-(3-플루오로페닐)-1,7-나프틸리딘-5-카복사마이드를 유효성분으로 포함하고,
혈전증, 동맥 혈전증, 정맥 혈전증, 간문맥 혈전증, 관상 및 뇌동맥 혈전증, 말초혈관 또는 심부정맥 혈전증, 폐동맥 색전증, 동맥 색전증, 뇌 색전증, 신장 색전증, 및 혈전 색전증으로 이루어진 군으로부터 선택되는 질환을 예방 또는 개선 하기 위한 건강기능식품.
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WO2019073253A1 (en) * | 2017-10-13 | 2019-04-18 | Imperial Innovations Limited | INHIBITORS OF MAP4K4 |
KR20190072011A (ko) | 2017-12-15 | 2019-06-25 | 충북대학교 산학협력단 | 나토키나제와 항염증제를 유효성분으로 포함하는 혈소판 응집 억제용 또는 혈전용해용 의약 조성물 |
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WO2019073253A1 (en) * | 2017-10-13 | 2019-04-18 | Imperial Innovations Limited | INHIBITORS OF MAP4K4 |
KR20190072011A (ko) | 2017-12-15 | 2019-06-25 | 충북대학교 산학협력단 | 나토키나제와 항염증제를 유효성분으로 포함하는 혈소판 응집 억제용 또는 혈전용해용 의약 조성물 |
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Journal of Biological Chemistry, 282(44), 31990-31999, 2007. * |
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