KR20200085782A - 비스테로이드성 선택적 글루코코르티코이드 수용체 효능작용 조절제 (segram) 및 이의 용도 - Google Patents
비스테로이드성 선택적 글루코코르티코이드 수용체 효능작용 조절제 (segram) 및 이의 용도 Download PDFInfo
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Abstract
(화학식 1).
본 발명은 또한 염증성 장애의 예방 또는 치료를 필요로 하는 대상체에서 염증성 장애의 예방 또는 치료에 사용하기 위한 화학식 1의 SEGRAM 또는 이의 유도체, 또는 이들의 약제학적으로 허용되는 에난티오머, 중수소화된 형태, 염, 용매화물 및/또는 전구약물에 관한 것이다.
Description
도 2는 (A) [(R/S)-5-[4-(5-플루오로-2-메톡시페닐)-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노]이소벤조푸란-1(3H)-온] [CpdX], 또는 (C) [(R/S)-5-{4-[2-(메톡시-D3)-5-플루오로페닐]-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노}이소벤조푸란-1(3H)-온] [CpdX-D3]의 합성에 대한 두 개의 개략도; 및 초임계 유체 크로마토그래피 (SFC) 방법을 통한 (B) [(R/S)-5-[4-(5-플루오로-2-메톡시페닐)-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노]-이소-벤조푸란-1(3H)-온] [CpdX], 또는 (D) [(R/S)-5-{4-[2-(메톡시-D3)-5-플루오로페닐]-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노}이소벤조푸란-1(3H)-온] [CpdX-D3]의 두 개의 에난티오머의 분리를 보여주는 두 개의 크로마토그램을 포함한다.
도 3은 (A) mTOR 억제제를 암호화하는 GR-전사촉진된 REDD1 유전자로부터; (B) GR 직접-전사억제된 케라틴 5 (K5) 유전자로부터; (C) GR 간접-전사억제된 인터류킨-1β (IL-1β) 유전자로부터; 및 (D) GR 간접-전사억제된 인터류킨-6 (IL-6) 유전자로부터 qRT-PCR 분석에 의해 측정된 (HPRT 하우스키핑 유전자와 비교하여) 나타낸 바와 같은 RNA 전사체의 발현을 보여주는 4개의 히스토그램의 세트이다. RNA 전사체는 (A 및 B의 경우) 에탄올 [비히클], 1 nmole/cm2의 덱사메타손 [Dex], Mapracorat, (R/S)-5-[4-(5-플루오로-2-메톡시페닐)-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노]이소벤조푸란-1(3H)-온 [CpdX], CpdX(eA), CpdX(eB), (R/S)-5-{4-[2-(메톡시-D3)-5-플루오로페닐]-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노}이소벤조푸란-1(3H)-온 [CpdX-D3], CpdX-D3(eA) 또는 CpdX-D3(eB); (C 및 D의 경우) (A 및 B)에서와 같지만 추가의 12-O-테트라데카노일포르볼-13-아세테이트 [TPA] 처리 (1 nmole/cm2)를 사용한 국소 18-시간-처리 후 마우스 귀로부터 추출하였다. 데이터는 처리당 적어도 3마리의 마우스로 적어도 3회의 독립적인 실험의 평균 ± SEM으로 표시된다.
도 4는 대식세포 염증성 단백질-1β [CCL4], 사이클로옥시게나제-2 [COX2], 콜라게나제 3 [MMP13], 인터류킨-1β [IL1β], 인터류킨-6 [IL6], 종양 괴사 인자 알파 [TNFα], 흉선 기질상 림포포이에틴 [TSLP], 인터류킨-22 [IL22] 및 인터류킨-23 [IL23]을 암호화하는 유전자의 RNA 전사체의 q-RT-PCR 분석에 의해 측정된 상대 RNA 발현을 보여주는 히스토그램이다. Th1-, Th2- 및 Th17-특이 전염증성 인터류킨이 강조된다. RNA 전사체는 12-O-테트라데카노일포르볼-13-아세테이트 단독 [TPA], TPA와 덱사메타손 [TPA+Dex], TPA와 (R/S)-5-[4-(5-플루오로-2-메톡시페닐)-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노]이소벤조푸란-1(3H)-온 [TPA+CpdX], 또는 TPA와 (R/S)-5-{4-[2-(메톡시-D3)-5-플루오로페닐]-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노}이소벤조푸란-1(3H)-온 [TPA+CpdX-D3]으로의 처리 (1 nmole/cm2)에 의한 접촉성 피부염-유사 염증의 유도 후 마우스 귀 피부 샘플로부터 추출하였다. 데이터는 처리당 적어도 3마리의 마우스로 적어도 3회의 독립적인 실험의 평균 ± SEM으로 표시된다.
도 5는 인터류킨-1β [IL1β], 인터류킨-6 [IL6], 사이클로옥시게나제-2 [COX2] 및 종양 괴사 인자 알파 [TNFα]를 암호화하는 유전자의 RNA 전사체의 q-RT-PCR 분석에 의해 측정된 상대 RNA 발현의 히스토그램이다. RNA 전사체는 도 4에 기술된 바와 같이 마우스 귀 피부 샘플로부터 추출하였다. 덱사메타손 [Dex], (R/S)-5-[4-(5-플루오로-2-메톡시페닐)-2-하이드록시-4-메틸-2-(트리플루오로메틸)-펜틸아미노]이소벤조푸란-1(3H)-온 [CpdX], 뿐만 아니라 (R/S)-5-{4-[2-(메톡시-D3)-5-플루오로페닐]-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노}-이소벤조푸란-1(3H)-온 [CpdX-D3]을 에탄올 (EtOH)(1 nmole/cm2) 또는 크림 (0.05%)으로 투여하였다. 데이터는 처리당 적어도 3마리의 마우스로 적어도 3회의 독립적인 실험의 평균 ± SEM으로 표시된다.
도 6은 도 5에서 처리된 바와 같은 마우스의 피부 절편을 보여주는 8개의 현미경 사진의 세트이다. 마우스 귀 피부 절편을 헤마톡실린 및 에오신으로 염색하였다. 기준자는 20 μm를 나타낸다.
도 7은 콜라게나제 3 [MMP13], 사이클로옥시게나제-2 [COX2], 인터류킨-1β [IL1β], 인터류킨-6 [IL6], 인터류킨-10 [IL10], 인터류킨-13 [IL13] 및 흉선 기질상 림포포이에틴 [TSLP]을 암호화하는 유전자의 RNA 전사체의 q-RT-PCR 분석에 의해 측정된 상대 RNA 발현을 보여주는 히스토그램이다. Th2-특이 전염증성 인터류킨이 강조된다. RNA 전사체는 아토피성 피부염-유사 염증의 유도 및 칼시포트리올 단독 [MC903], 칼시포트리올과 덱사메타손 [MC903+Dex], 칼시포트리올과 (R/S)-5-[4-(5-플루오로-2-메톡시페닐)-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노]이소벤조푸란-1(3H)-온 [MC903+CpdX], 칼시포트리올과 CpdX(eA) [MC903+CpdX(eA)], 칼시포트리올 및 CpdX(eB) [MC903+CpdX(eB)], 칼시포트리올과 (R/S)-5-{4-[2-(메톡시-D3)-5-플루오로페닐]-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노}이소벤조푸란-1(3H)-온 [MC903+CpdX-D3], 칼시포트리올과 CpdX-D3(eA) [MC903+CpdX-D3(eA)] 또는 칼시포트리올과 CpdX-D3(eB) [MC903+CpdX-D3(eB)]으로의 처리 (1 nmole/cm2) 후 마우스 귀 피부 샘플로부터 추출하였다. 데이터는 처리당 적어도 3마리의 마우스로 적어도 3회의 독립적인 실험의 평균 ± SEM으로 표시된다.
도 8은 도 7에서와 같이 처리된 마우스의 피부 절편을 보여주는 8개의 현미경 사진의 세트이다. 마우스 귀 피부 절편을 헤마톡실린 및 에오신으로 염색하였다. 기준자는 20 μm를 나타낸다.
도 9는 (A) 기관지폐포 세척액 [BAL]에서의 세포 수 및 (B) 난백알부민 (OVA)에 의한 18일의 감작에 이은 OVA를 단독으로 [OVA] 또는 1 mg/kg 체중의 덱사메타손 [OVA+Dex] 또는 (R/S)-5-[4-(5-플루오로-2-메톡시페닐)-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노]이소벤조푸란-1(3H)-온 [OVA+CpdX]과 함께 사용한 3일간의 챌린지를 포함하는 천식-유사 폐 염증의 22일 유도 후 마우스 폐 샘플로부터 추출된 RNA 전사체의 q-RT-PCR 분석에 의해 측정된 상대 RNA 발현을 보여주는 두 개의 히스토그램의 세트이다. (A): 총 세포, 호산구, 호중구, 대식세포 및 림프구의 수 (x105)가 보고된다. (B): 인터류킨-1β [IL1β], 인터류킨-6 [IL6], 인터류킨-4 [IL4], 인터류킨-5 [IL5], 인터류킨-10 [IL10], 인터류킨-13 [IL13], 에오탁신 [Eotaxin], 대식세포 염증성 단백질-1β [CCL4] 및 종양 괴사 인자 알파 [TNFα]를 암호화하는 유전자의 상대 RNA 발현이 보고된다. Th2- 및 Th1-특이 전염증성 인터류킨이 강조된다. 데이터는 처리당 적어도 6마리의 마우스의 평균 ± SEM로 표시된다. OVA 처리와 비교한 통계적 유의도는 스튜던트 t 검정에 의해 계산하였다; (*) p<0,05; (**) p<0,01; (***) p<0,001.
도 10은 도 9에 기술된 바와 같이 난백알부민 (OVA)에 의한 18일의 감작에 이은 3일간의 챌린지 후 난백알부민-유도된 천식-유사 폐 염증을 보여주는 3개의 현미경 사진의 세트이다. 폐 절편을 헤마톡실린 및 에오신으로 염색하였다. 기관지주위 (B) 및 혈관주위 (V) 영역이 표시된다. 기준자는 40 μm를 나타낸다.
도 11은 (A-B) 기관지폐포 세척액 [BAL]에서의 세포 수 및 (C-D) 집먼지 진드기 (HDM)로의 28일 감작에 이은 3일간의 HDM 챌린지를 단독으로 [HDM] 또는 1 mg/kg 체중의 덱사메타손 [HDM+Dex], (R/S)-5-[4-(5-플루오로-2-메톡시페닐)-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노]이소벤조푸란-1(3H)-온 [HDM+CpdX], CpdX(eA) [HDM+CpdX(eA)], CpdX(eB) [HDM+CpdX(eB)], (R/S)-5-{4-[2-(메톡시-D3)-5-플루오로페닐]-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노}이소벤조푸란-1(3H)-온 [HDM+CpdX-D3], CpdX-D3(eA) [HDM+CpdX-D3(eA)] 또는 CpdX-D3(eB) [HDM+CpdX-D3(eB)]과 함께 사용한 천식-유사 폐 염증의 유도 후 D32에서 마우스 폐 샘플로부터 추출된 RNA 전사체의 q-RT-PCR 분석에 의해 측정된 상대 RNA 발현을 보여주는 4개의 히스토그램의 세트이다. (A-B): 총 세포, 호산구, 호중구, 대식세포 및 림프구의 수 (x105)가 보고된다. (C-D): 인터류킨-1β [IL1β], 인터류킨-6 [IL6], 인터류킨-4 [IL4], 인터류킨-5 [IL5], 인터류킨-13 [IL13], 에오탁신 [Eotaxin] 및 대식세포 염증성 단백질-1β [CCL4]를 암호화하는 유전자의 상대 RNA 발현이 보고된다. Th2-특이 전염증성 인터류킨이 강조된다. 데이터는 처리당 적어도 4마리의 마우스로 적어도 3회 독립적인 실험의 평균 ± SEM로 표시된다. HDM 처리와 비교한 통계적 유의도는 스튜던트 t 검정에 의해 계산하였다; (*) p<0,05; (**) p<0,01; (***) p<0,001; (ns) 유의하지 않음.
도 12는 HDM에 의한 28일의 감작에 이은 도 11에 기술된 바와 같은 3일간의 챌린지 후 집먼지 진드기 (HDM)-유도된 천식-유사 폐 염증을 보여주는 8개의 현미경 사진의 세트이다. 폐 절편을 헤마톡실린 및 에오신으로 염색하였다. 기관지주위 (B) 및 혈관주위 (V) 영역이 표시된다. 기준자는 40 μm를 나타낸다.
도 13은 집먼지 진드기 (HDM)-유도된 천식-유사 폐 염증이 HDM으로의 28일의 감작에 이은 도 11에 기술된 바와 같은 3일간의 챌린지에 의해 유도된 마우스의 메타콜린 (MCh, 50 mg/mL)에 대한 기도 과민반응성을 보여주는 두 개의 히스토그램의 세트이다. (A) 기도 저항성, (B) 기도 탄력성. 데이터는 처리당 적어도 8마리의 마우스를 사용한 평균 ± SEM로 표시된다. HDM 처리 자체와 비교한 통계적 유의도는 이원 ANOVA에 이은 본페로니 다중 비교를 통해 계산하였다; (**) p<0,01; (***) p<0,001; (****) p<0,0001; (ns) 유의하지 않음.
도 14는 인터류킨-17a [IL17a], 인터류킨-17c [IL17c], 인터류킨-17f [IL17f] 및 인터류킨-22 [IL22]를 암호화하는 유전자의 RNA 전사체의 q-RT-PCR 분석에 의해 측정된 상대 RNA 발현을 보여주는 히스토그램이다. RNA 전사체는 에탄올 [Aldara+비히클], 1 nmole/cm2 덱사메타손 [Aldara+Dex], (R/S)-5-[4-(5-플루오로-2-메톡시페닐)-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노]이소벤조푸란-1(3H)-온 [Aldara+CpdX], (R/S)-5-{4-[2-(메톡시-D3)-5-플루오로페닐]-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노}이소벤조푸란-1(3H)-온 [Aldara+ CpdX-D3]으로의 마지막 5일간의 국소 처리를 포함한 Aldara®-유도된 건선-유사 염증의 9일 유도 후 마우스 귀 피부 샘플로부터 추출하였다. Th17-특이 전염증성 인터류킨이 강조된다. 데이터는 처리당 적어도 3마리의 마우스로 적어도 3회의 독립적인 실험의 평균 ± SEM으로 표시된다.
도 15는 도 14에 기술된 바와 같은 5일 국소 처리 후 Aldara®-생성된 건선-유사 피부 염증을 보여주는 5개의 현미경 사진의 세트이다. 마우스 귀 피부 샘플을 헤마톡실린 및 에오신으로 염색하였다. 기준자는 20 μm를 나타낸다.
도 16은 콜라겐-유도된 관절염-유사 염증이 유발되고 (T0, 좌측 패널), NaCl 0,9% [비히클], 1 mg/kg 체중의 덱사메타손 [Dex], (R/S)-5-[4-(5-플루오로-2-메톡시페닐)-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노]이소벤조푸란-1(3H)-온 [CpdX], (R/S)-5-{4-[2-(메톡시-D3)-5-플루오로페닐]-2-하이드록시-4-메틸-2-(트리플루오로메틸)-펜틸아미노}이소벤조푸란-1(3H)-온 [CpdX-D3]으로의 10일 (T10) 복강내 투여 (오른쪽 패널)로 처리된 마우스의 뒷발을 보여주는 8개의 현미경 사진의 세트이다.
도 17은 관절염-유사 염증의 유도 (T0에서) 및 (A) NaCl 0,9% [비히클], 1 mg/kg 체중의 덱사메타손 [Dex], (R/S)-5-[4-(5-플루오로-2-메톡시페닐)-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노]이소벤조푸란-1(3H)-온 [CpdX] 또는 (R/S)-5-{4-[2-(메톡시-D3)-5-플루오로페닐]-2-하이드록시-4-메틸-2-(트리플루오로메틸)-펜틸아미노}이소벤조푸란-1(3H)-온 [CpdX-D3]; 및 (B) [CpdX-(eA)], [CpdX(eB)], [CpdX-D3(eA)] 또는 [CpdX-D3(eB)]로의 10일간의 복강내 투여 (T10) 후 마우스의 뒷발 (발목 수준에서)의 두께 (mm 단위)를 보여주는 2개의 그래프의 세트이다. 데이터는 처리당 적어도 6마리의 마우스를 사용한 평균 ± SEM으로 표시된다. Dex 처리와 비교한 통계적 유의도는 스튜던트 t 검정에 의해 계산하였다. (*) p<0,05; (ns)는 Dex-처리된, CpdX-처리된 및 CpdX-D3-처리된 마우스 사이에 관찰된 차이가 유의하지 않음을 나타낸다.
도 18은 인터류킨-1β [IL1β], 인터류킨-6 [IL6], 인터류킨-17a [IL17a], 인터류킨-17f [IL17f] 및 종양 괴사 인자 알파 [TNFα]의 RNA 전사체의 q-RT-PCR 분석에 의해 측정된 상대 RNA 발현을 보여주는 히스토그램이다. 총 RNA 전사체는 도 17에 기술된 바와 같은 10일 처리 전 (T0) 또는 10일 처리 후 (T10) 마우스 전체 뒷발로부터 추출하였다. Th17- 및 Th1-특이 전염증성 인터류킨이 강조된다. 데이터는 처리당 적어도 6마리의 마우스를 사용한 평균 ± SEM으로 표시된다.
도 19는 정상 결장 절편 [DSS 처리 없음] 및 NaCl 0,9% [DSS+비히클], 1 mg/kg 체중의 덱사메타손 [DSS+Dex], (R/S)-5-[4-(5-플루오로-2-메톡시-페닐)-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노]-이소벤조푸란-1(3H)-온 [DSS+CpdX] 또는 (R/S)-5-{4-[2-(메톡시-D3)-5-플루오로-페닐]-2-하이드록시-4-메틸-2-(트리플루오로메틸)-펜틸아미노}이소벤조푸란-1(3H)-온 [DSS+CpdX-D3]의 복강내 투여로 D11, D12 및 D13에 처리된 마우스로부터의 절편과 비교하여 13일 DSS (3% 덱스트란 나트륨 설페이트) 처리에 의해 유도된 궤양성 대장염을 보여주는 결장 절편 (각각 50 μm 또는 20 μm을 나타내는 기준자로 2배 확대)의 10개의 현미경 사진의 세트이다. 결장 절편은 초기에 헤마톡실린 및 에오신으로 염색하였다. 실선 화살표: 점막 염증 세포 침윤; 점선 화살표: 점막하 염증성 세포 침윤; 화살촉 : 궤양화.
도 20은 인터류킨-1β [IL1β], 인터류킨-6 [IL6], 인터류킨-17a [IL17a], 인터류킨-17f [IL17f], 흉선 기질상 림포포이에틴 [TSLP] 및 콜라게나제 3 [MMP13]을 암호화하는 유전자의 RNA 전사체의 비교 q-RT-PCR 분석을 보여주는 히스토그램이다. Th17- 및 Th2-특이 전염증성 인터류킨이 강조된다. RNA 전사체는 D11, D12 및 D13에 NaCl 0,9% [DSS+비히클], 1 mg/kg 체중의 덱사메타손 [DSS+Dex], (R/S)-5-[4-(5-플루오로-2-메톡시페닐)-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노]-이소벤조푸란-1(3H)-온 [DSS+CpdX], CpdX(eA) [DSS+CpdX(eA)], CpdX(eB) [DSS+CpdX(eB)], (R/S)-5-{4-[2-(메톡시-D3)-5-플루오로페닐]-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노}이소벤조푸란-1(3H)-온 [DSS+CpdX-D3], CpdX-D3(eA) [DSS+CpdX-D3(eA)] 또는 CpdX-D3(eB) [DSS+CpdX-D3(eB)]의 복강내 투여와 함께 13일 동안의 (식수 중의) 3% DSS로 경구-처리된 마우스의 결장 샘플로부터 추출하였다. 데이터는 처리당 적어도 4마리의 마우스로 적어도 3회의 독립적인 실험의 평균 ± SEM으로 표시된다.
도 21은 (A) 14일의 OVA 감작에 이은 NaCl 0,9% (비히클) 또는 OVA로의 10일 챌린지를 포함하는 난백알부민 (OVA)-유도된 알레르기성 결막염의 유도시, 24일째 마지막 처리한지 20분 후 마우스 눈의 임상적 외관을 보여주는 9개의 현미경 사진의 세트이다. 22, 23 및 24일째에, OVA-챌린지된 마우스 눈을 NaCl 0,9% [OVA], 0.1%의 덱사메타손 [OVA+Dex], (R/S)-5-[4-(5-플루오로-2-메톡시페닐)-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노]이소벤조푸란-1(3H)-온 [OVA+CpdX], CpdX-(eA) [OVA+CpdX(eA)], CpdX(eB) [OVA+CpdX(eB)], (R/S)-5-{4-[2-(메톡시-D3)-5-플루오로페닐]-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노}이소벤조푸란-1(3H)-온 [OVA+CpdX-D3], CpdX-D3(eA) [OVA+CpdX-D3(eA)] 또는 CpdX-D3(eB) [OVA+CpdX-D3(eB)]로 공동-처리하였다; 및 (B) (A) 하에 기술된 바와 같이 처리된 마우스 눈의 임상 스코어 (결막성 충혈, 눈꺼풀 부종 및 눈물)를 보여주는 그래프이다. 스코어링을 수행하였으며, 각 파라미터는 0 내지 3의 범위로 등급을 매겼다 (0 = 부재, 1 = 경미, 2 = 중등도 및 3 = 중증 증상). 따라서, 각각의 동물은 0 내지 9 범위의 총 임상 스코어를 받았으며, 데이터는 처리당 적어도 4마리의 마우스를 사용한 평균 ± SEM으로 표현되었다.
도 22는 (A) Kindlin-1 (nGRE-함유 유전자) 및 (B) REDD1 (+GRE-함유 유전자) 유전자의 RNA 전사체의 (q-RT-PCR 분석에 의해 측정된) 상대 발현을 보여주는 두 개의 히스토그램의 세트이다. 마우스를 등 피부를 면도한 다음 에탄올 [비히클], 1 nmole/cm2의 덱사메타손 [Dex], (R/S)-5-[4-(5-플루오로-2-메톡시페닐)-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노]-이소벤조푸란-1(3H)-온 [CpdX], [CpdX(eA)], [CpdX(eB)], (R/S)-5-{4-[2-(메톡시-D3)-5-플루오로페닐]-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노}-이소벤조푸란-1-(3H)-온 [CpdX-D3], [CpdX-D3(eA)] 또는 [CpdX-D3(eB)]로 8일간 국소 처리하였다. 데이터는 처리당 적어도 3마리의 마우스로 적어도 3회의 독립적인 실험의 평균 ± SEM으로 표시된다.
도 23은 등 피부를 면도한 다음 도 22에 기술된 바와 같이 8일 동안 국소 처리한 마우스에서 표피 두께 (μm 단위)의 형태적 분석을 보여주는 히스토그램이다. 데이터는 처리당 적어도 3마리의 마우스로 적어도 3회의 독립적인 실험의 평균 ± SEM으로 표시된다.
도 24는 등 피부를 면도한 다음 도 22에 기술된 바와 같이 국소 처리한 마우스에서 피부 위축을 보여주는 16개의 현미경 사진의 세트이다. 좌측 패널: 피부 샘플을 헤마톡실린 및 에오신으로 염색하였다. 우측 패널: 핵을 DAPI로 염색하였다. 기준자는 20 μm를 나타낸다.
도 25는 마이크로CT에 의해 측정된 5개의 피질 골 파라미터에 대한 10개의 그래프의 세트이다 : (A) 골 용적/총 용적 (%); (B) 피질 두께 (mm); (C) 총 면적 (mm2); (D) 골 면적 (mm2) 및 (E) 골수 면적 (mm2). 8주령 마우스를 NaCl 0,9% [비히클], 1 mg/kg 체중의 덱사메타손 [Dex], (R/S)-5-[4-(5-플루오로-2-메톡시페닐)-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노]이소벤조푸란-1(3H)-온 [CpdX], [CpdX(eA)], [CpdX(eB)], (R/S)-5-{4-[2-(메톡시-D3)-5-플루오로페닐]-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노}이소벤조푸란-1(3H)-온 [CpdX-D3], [CpdX-D3(eA)] 또는 [CpdX-D3(eB)]의 매일 피하 주사로 3개월 동안 처리하였다. FX 양자 마이크로-CT 스캐너 (Perkin Elmer)를 사용하여 경골 중간축에서 측정을 수행하였다. 데이터는 처리당 적어도 6마리의 마우스에 대한 평균 (화살촉에 의해 표시됨) ± SEM에 해당한다. 비히클 처리와 비교한 통계적 유의도는 일원 ANOVA 검정에 이은 Dunnett의 다중 비교 검정을 통해 계산하였다; (*) p<0,05; (**) p<0,01 (***) p<0,001; (****) p<0,0001; (ns): 유의하지 않음.
도 26은 마우스 경골에서 Wnt16 유전자의 RNA 전사체의 (q-RT-PCR 분석에 의해 측정된) 상대 발현을 보여주는 히스토그램이다. 8주령 마우스를 도 25에 나타낸 바와 같이 처리하였다. 데이터는 처리당 적어도 6마리의 마우스를 사용한 평균 ± SEM으로 표시된다.
도 27은 NaCl 0,9% [비히클], 1 mg/kg 체중의 덱사메타손 [Dex], (R/S)-5-[4-(5-플루오로-2-메톡시페닐)-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노]이소벤조푸란-1(3H)-온 [CpdX] 또는 (R/S)-5-{4-[2-(메톡시-D3)-5-플루오로페닐]-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노}이소벤조푸란-1(3H)-온 [CpdX-D3]의 매일 피하 주사로 추가 3개월 동안 제시된 바와 같이 처리된 8주령 마우스의 (A) 체중, (B) 지방 퍼센트 및 (C) 제지방 퍼센트의 (처리 전) 기준선으로부터의 변화를 보여주는 3개의 그래프의 세트이다. 데이터는 처리당 적어도 9마리의 마우스에 대한 (화살촉이 가리키는 바와 같은) 평균 ± SEM에 해당한다. 통계적 유의도는 Krustal-Walis 검정에 이은 Dunn의 다중 비교 검정를 통해 계산하였다; (*) p<0,05; (**) p<0,01 (***) p<0,001.
도 28은 NaCl 0,9% [비히클], 1 mg/kg 체중의 덱사메타손 [Dex] 또는 (R/S)-5-[4-(5-플루오로-2-메톡시페닐)-2-하이드록시-4-메틸-2-(트리플루오로메틸)펜틸아미노]이소벤조푸란-1(3H)-온 [CpdX], [CpdX(eA)], [CpdX-(eB)], (R/S)-5-{4-[2-(메톡시-D3)-5-플루오로페닐]-2-하이드록시-4-메틸-2-(트리플루오로-메틸)펜틸아미노}이소벤조푸란-1(3H)-온 [CpdX-D3], [CpdX-D3(eA)] 또는 [CpdX-D3(eB)]의 매일 피하 주사로 추가 3개월 동안 처리된 8주령 마우스의 (A) 흉선, (B) 비장, (C) 부신 및 (D) 신장의 중량 (그램 단위)을 보여주는 4개의 히스토그램의 세트이다. 데이터는 처리당 적어도 9마리의 마우스에 대한 평균 ± SEM로 표시된다. 통계적 유의도는 스튜던트 t 검정에 의해 계산하였다; (*) p<0,05.
도 29는 도 27에 나타낸 바와 같이 처리된 8주령 마우스의 부신의 절편을 보여주는 (기준자가 각각 50 μm 또는 25 μm을 나타내는 두 개의 상이한 배율에서) 8개의 현미경 사진의 세트이다. 부신의 피질 층은 양방향 화살표로 왼쪽 패널에 표시되는 반면 피질의 속상대 및 구상대는 각각 오른쪽 패널에 긴 굵은 양방향 화살표 및 작은 빈 양방향 화살표로 표시된다.
도 30은 도 28에 나타낸 바와 같이 처리된 8주령 마우스에서의 코르티코스테론 합성을 보여준다. (A): 스테로이드 11α-하이드록실라제 (Cyp11a), 스테로이드 11β-하이드록실라제 (Cyp11b1), 3β-하이드록시스테로이드 데하이드로게나제 (HSD3β) 및 알도스테론 신타제 (Cyp11b2) 유전자의 (q-RT-PCR 분석에 의해 결정된 바와 같은) RNA 전사체의 마우스 부신에서의 상대 발현; (B): 제시된 바와 같이 처리된 마우스에서 10 a.m. 및 6 p.m.의 혈장 코르티코스테론 수준. 데이터는 처리당 적어도 9마리의 마우스에 대한 평균 ± SEM로 표시된다.
도 31은 도 28에 나타낸 바와 같이 처리된 8주령 마우스에서의 혈중 글루코스 수준 (mg/dL)을 보여주는 두 개의 히스토그램의 세트이다. (A) : 밤새 14시간 금식 후 혈장 글루코스 수준; (B): 글루코스 i.p. 주사 (2 mg/kg 체중) 후 2시간 복강내 글루코스 내성 검사 (IPGTT). 데이터는 처리당 적어도 6마리의 마우스에 대한 평균 ± SEM로 표시된다. 비히클 처리와 비교한 통계적 유의도는 스튜던트 t 검정에 의해 계산하였다; (*) p<0,05; (**) p<0,01.
도 32(A)는 도 28에 나타낸 바와 같이 처리된 8주령 마우스에서의 혈중 인슐린 수준 (μg/L)을 보여주는 히스토그램이다. 데이터는 처리당 적어도 9마리의 마우스에 대한 평균 ± SEM로 표시된다. (B): 0,75 U 인슐린/kg 체중의 복강내 주사 후 1시간 복강내 인슐린 내성 검사 (IPITT). 데이터는 처리당 적어도 6마리의 마우스에 대한 평균 ± SEM로 표시된다. 비히클 처리와 비교한 통계적 유의도는 스튜던트 t 검정에 의해 계산하였다, * p<0,01. (C): 세린 318에서 인산화된 포스 포-인슐린 수용체 기질-1 (p-IRS1 S318), pan-인슐린 수용체 기질-1 (IRS 총), 세린 473에서 인산화된 포스포-단백질 키나제 B (p-AKT S473) 및 pan-단백질 키나제 B (AKT 총) 단백질에 대한 마우스 간 샘플의 웨스턴 블롯 분석.
도 33은 도 28에 나타낸 바와 같이 처리된 8주령 마우스의 간에서 (동결된 간 절편의 5% 레드 오일 염색에 의해 밝혀진) 선택적 지질 침착을 보여주는 (2배율에서의) 16개의 현미경 사진의 세트이다.
도 34는 마우스 간에서 지방산 신타제 (FASN) 및 스테아로일-CoA 탈포화효소-1 (SCD1)의 전사체의 상대 RNA 발현 (q-RT-PCR 분석)을 보여주는 두 개의 히스토그램의 세트이다. 8주령 마우스를 도 28에 나타낸 바와 같이 처리하였다. 데이터는 처리당 적어도 9마리의 마우스에 대한 평균 ± SEM에 해당한다. 통계적 유의도는 스튜던트 t 검정에 의해 계산하였다; (**) p<0,01; (***) p<0,001.
도 35는 도 28에 나타낸 바와 같이 처리된 8주령 마우스로부터의 혈액에서 총 콜레스테롤 수준 (mmol/L) 및 담즙산 수준 (μmol/L)을 보여주는 두 개의 히스토그램의 세트이다. 데이터는 처리당 적어도 9마리의 마우스에 대한 평균 ± SEM으로 표시된다.
Claims (21)
- 제1항 또는 제2항에 있어서, SEGRAM이 라세미 형태(racemic form)이거나, 이의 두 개의 에난티오머 형태 중의 하나인, SEGRAM 또는 이의 유도체.
- 제1항 내지 제4항 중의 어느 한 항에 있어서, SEGRAM이 글루코코르티코이드 수용체의 직접 전사촉진 (transactivation) 기능 또는 직접 전사억제 (transrepression) 기능 중 어느 것도 유도하지 않거나 실질적으로 유도하지 않는, SEGRAM 또는 이의 유도체.
- 제1항 내지 제5항 중의 어느 한 항에 있어서, SEGRAM이 이를 필요로 하는 대상체에 투여시 스테로이드성 항염증 약물 (SAID)-관련 부작용을 유도하지 않거나 실질적으로 유도하지 않는, SEGRAM 또는 이의 유도체.
- 제6항에 있어서, SAID-관련 부작용이 피부 위축 (skin atrophy); 골다공증 (osteoporosis); 성장 억제; 체중 손실; 지방량 증가; 제지방 손실; 흉선, 비장, 신장 및/또는 부신 아폽토시스(apoptosis); 코르티코스테론 합성 억제; 부신 억제; 고혈당증; 인슐린 내성; 고인슐린혈증 및 지방간을 포함하는 그룹으로부터 선택되는, SEGRAM 또는 이의 유도체.
- 제1항 내지 제7항 중의 어느 한 항에 있어서, 염증성 장애가 IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17a, IL-17c, IL-17f, IL-18, IL-21, IL-22, IL-23, IL-33, TSLP, TGFβ, CCL4, TNFα, MMP13, IgE, IgG1 및 IgG2a를 포함하는 그룹으로부터 선택된 적어도 하나의 분비된 사이토카인 및/또는 항체의 증가된 수준을 특징으로 하는, SEGRAM 또는 이의 유도체.
- 제1항 내지 제8항 중의 어느 한 항에 있어서, 염증성 장애가 아토피성 피부염 (atopic dermatitis), 접촉성 피부염 (contact dermatitis), 알레르기성 천식 (allergic asthma), 알레르기성 부비동염 (allergic sinusitis), 알레르기성 결막염 (allergic conjunctivitis), 알레르기성 비염 (allergic rhinitis), 비결막염 (rhinoconjunctivitis), 거대-세포 동맥염 (giant-cell arteritis) (호턴병(Horton disease)), 건초열 (hay fever), 일광성 피부염 (solar dermatitis), 습진 (eczema), 두드러기 (urticaria), 혈관부종 (angioedema), 결절성 홍반 (erythema nodosum), 다형 홍반 (erythema multiforme), 피부 괴사성 세정맥염 (cutaneous necrotizing venulitis), 곤충 물린 피부 염증 (insect bite skin inflammation), 아나필락시스 (anaphylaxis), 건선 (psoriasis), 류마티스 관절염 (rheumatoid arthritis), 염증성 장 질환 (inflammatory bowel disease; IBD) (크론병, 궤양성 대장염 및 대장염 포함), 치주염 (periodontitis), 만성 염증성 질환 (chronic inflammatory disease), 홍반성 낭창 (lupus erythematosus), 피부근염 (dermatomyositis), 혈관염 (vasculitis), 쇼그렌 증후군 (Sjogren's syndrome), 경피증 (scleroderma), 다발성 경화증 (multiple sclerosis), 백반증 (vitiligo), 편평 태선 (lichen planus), 2형 당뇨병 (type 2 diabete), 관상 동맥 심장 질환 (coronary heart disease), 고지혈증 (hyperlipidemia), 폐경기-유도된 대사 증후군 (postmenopausal-induced metabolic syndrome) 및 지방증 (steatosis), 및 이식편 대 숙주 질환 (graft-versus-host disease)을 포함하는 그룹으로부터 선택되는, SEGRAM 또는 이의 유도체.
- 제1항 내지 제9항 중의 어느 한 항에 있어서, 염증성 장애가 아토피성 피부염 (atopic dermatitis), 접촉성 피부염 (contact dermatitis), 알레르기성 천식 (allergic asthma), 건선 (psoriasis), 알레르기성 결막염 (allergic conjunctivitis), 류마티스 관절염 (rheumatoid arthritis) 및 궤양성 대장염 (ulcerative colitis)을 포함하는 그룹으로부터 선택되는, SEGRAM 또는 이의 유도체.
- 제1항 내지 제10항 중의 어느 한 항에 있어서, 염증성 장애가 아토피성 피부염 (atopic dermatitis), 접촉성 피부염 (contact dermatitis), 알레르기성 천식 (allergic asthma), 건선 (psoriasis), 알레르기성 결막염 (allergic conjunctivitis), 류마티스 관절염 (rheumatoid arthritis) 및 궤양성 대장염 (ulcerative colitis)을 포함하는 그룹으로부터 선택되고; SEGRAM이 화학식 1의 SEGRAM 또는 이의 유도체의 에난티오머이고, 상기 에난티오머가 화학식 1의 SEGRAM 또는 이의 유도체의 라세미 혼합물의 초임계 유체 크로마토그래피 (SFC)의 첫 번째 용출 피크 [CpdX(eA)]에 해당하는, SEGRAM 또는 이의 유도체.
- 제1항 내지 제10항 중의 어느 한 항에 있어서, 염증성 장애가 아토피성 피부염 (atopic dermatitis), 접촉성 피부염 (contact dermatitis), 건선 (psoriasis), 알레르기성 결막염 (allergic conjunctivitis), 및 궤양성 대장염 (ulcerative colitis)을 포함하는 그룹으로부터 선택되고; SEGRAM이 화학식 1의 SEGRAM 또는 이의 유도체의 에난티오머이고, 상기 에난티오머가 화학식 1의 SEGRAM 또는 이의 유도체의 라세미 혼합물의 초임계 유체 크로마토그래피 (SFC)의 두 번째 용출 피크 [CpdX(eB)]에 해당하는, SEGRAM 또는 이의 유도체.
- 제2항 내지 제10항 중의 어느 한 항에 있어서, 염증성 장애가 아토피성 피부염 (atopic dermatitis), 접촉성 피부염 (contact dermatitis), 알레르기성 천식 (allergic asthma), 건선 (psoriasis), 알레르기성 결막염 (allergic conjunctivitis), 류마티스 관절염 (rheumatoid arthritis) 및 궤양성 대장염 (ulcerative colitis)을 포함하는 그룹으로부터 선택되고; SEGRAM이 화학식 2의 SEGRAM 또는 이의 유도체의 에난티오머이고, 상기 에난티오머가 화학식 2의 SEGRAM 또는 이의 유도체의 라세미 혼합물의 초임계 유체 크로마토그래피 (SFC)의 첫 번째 용출 피크 [CpdX-D3(eA)]에 해당하는, SEGRAM 또는 이의 유도체.
- 제2항 내지 제10항 중의 어느 한 항에 있어서, 염증성 장애가 아토피성 피부염 (atopic dermatitis), 접촉성 피부염 (contact dermatitis), 건선 (psoriasis), 알레르기성 결막염 (allergic conjunctivitis), 및 궤양성 대장염 (ulcerative colitis)을 포함하는 그룹으로부터 선택되고; SEGRAM이 화학식 2의 SEGRAM 또는 이의 유도체의 에난티오머이고, 상기 에난티오머가 화학식 2의 SEGRAM 또는 이의 유도체의 라세미 혼합물의 초임계 유체 크로마토그래피 (SFC)의 두 번째 용출 피크 [CpdX-D3(eB)]에 해당하는, SEGRAM 또는 이의 유도체.
- 화학식 1의 선택적 글루코코르티코이드 수용체 효능작용 조절제 (SEGRAM) 또는 이의 유도체의 에난티오머 (바람직하게는 상기 에난티오머는 CpdX(eA) 또는 CpdX(eB)이다), 또는 이의 약제학적으로 허용되는 염, 용매화물 및/또는 전구약물.
- 제15항에 있어서, 상기 에난티오머가 초임계 유체 크로마토그래피 (SFC)에 의한 화학식 1의 화합물 또는 이의 유도체의 라세미 혼합물의 분리에 의해 수득되고, CpdX(eA)가 첫 번째 용출 피크에 해당하고 CpdX(eB)가 두 번째 용출 피크에 해당하는, 화학식 1의 SEGRAM 또는 이의 유도체의 에난티오머.
- 화학식 1의 선택적 글루코코르티코이드 수용체 효능작용 조절제 (SEGRAM) 또는 이의 유도체의 중수소화된 형태, 또는 이의 약제학적으로 허용되는 염, 용매화물 및/또는 전구약물.
- 제17항 또는 제18항에 있어서, 상기 중수소화된 형태가 라세미 형태인, 화학식 1의 SEGRAM 또는 이의 유도체의 중수소화된 형태.
- 제17항 또는 제18항에 있어서, 상기 중수소화된 형태가 화학식 2의 화합물의 두 개의 에난티오머 중 하나이고, 바람직하게는 상기 에난티오머가 CpdX-D3(eA) 또는 CpdX-D3(eB)인, 화학식 1의 SEGRAM 또는 이의 유도체의 중수소화된 형태.
- 제20항에 있어서, 상기 에난티오머가 초임계 유체 크로마토그래피 (SFC)에 의한 화학식 2의 화합물 또는 이의 유도체의 라세미 혼합물의 분리에 의해 수득되고, CpdX-D3(eA)가 첫 번째 용출 피크에 해당하고 CpdX-D3(eB)이 두 번째 용출 피크에 해당하는, 화학식 1의 SEGRAM 또는 이의 유도체의 중수소화된 형태.
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EP18305612.6 | 2018-05-17 | ||
PCT/EP2018/079049 WO2019081517A2 (en) | 2017-10-27 | 2018-10-23 | NON-STEROIDIC GLUCOCORTICOIC RECEPTOR (SEGRAM) RECEPTOR AGONIST MODULATORS AND USES THEREOF |
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KR1020207014598A Ceased KR20200085782A (ko) | 2017-10-27 | 2018-10-23 | 비스테로이드성 선택적 글루코코르티코이드 수용체 효능작용 조절제 (segram) 및 이의 용도 |
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US (1) | US11179363B2 (ko) |
EP (2) | EP3569228A1 (ko) |
JP (1) | JP2021509411A (ko) |
KR (1) | KR20200085782A (ko) |
CN (1) | CN111511359A (ko) |
AU (1) | AU2018355698A1 (ko) |
BR (1) | BR112020008350A2 (ko) |
MA (1) | MA50443A (ko) |
PT (1) | PT3700513T (ko) |
Families Citing this family (1)
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US12150922B1 (en) | 2023-12-08 | 2024-11-26 | King Faisal University | Methods of inhibiting cyclooxygenase (COX) using tolterodine |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
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US5262165A (en) | 1992-02-04 | 1993-11-16 | Schering Corporation | Transdermal nitroglycerin patch with penetration enhancers |
US6010715A (en) | 1992-04-01 | 2000-01-04 | Bertek, Inc. | Transdermal patch incorporating a polymer film incorporated with an active agent |
HU228434B1 (en) | 1995-06-07 | 2013-03-28 | Ortho Mcneil Pharm Inc | Transdermal medicament for administering 17-deacetyl norgestimate alone or in combination with an estrogen |
DE19723722A1 (de) * | 1997-05-30 | 1998-12-10 | Schering Ag | Nichtsteroidale Gestagene |
US6245804B1 (en) | 1997-05-30 | 2001-06-12 | Schering Aktiengesellschaft | Nonsteroidal gestagens |
US5948433A (en) | 1997-08-21 | 1999-09-07 | Bertek, Inc. | Transdermal patch |
DE19856475A1 (de) * | 1998-11-27 | 2000-05-31 | Schering Ag | Nichtsteroidale Entzündungshemmer |
DE10038639A1 (de) * | 2000-07-28 | 2002-02-21 | Schering Ag | Nichtsteroidale Entzündungshemmer |
ES2932076T3 (es) * | 2017-10-27 | 2023-01-11 | Association Pour La Rech A Ligbmc Ari | Moduladores agonistas de los receptores de glucocorticoides selectivos (SEGRAM) no esteroideos y usos de los mismos |
-
2018
- 2018-05-17 EP EP18305612.6A patent/EP3569228A1/en not_active Withdrawn
- 2018-10-23 AU AU2018355698A patent/AU2018355698A1/en not_active Abandoned
- 2018-10-23 JP JP2020543706A patent/JP2021509411A/ja active Pending
- 2018-10-23 KR KR1020207014598A patent/KR20200085782A/ko not_active Ceased
- 2018-10-23 BR BR112020008350-0A patent/BR112020008350A2/pt not_active Application Discontinuation
- 2018-10-23 EP EP18786823.7A patent/EP3700513B1/en active Active
- 2018-10-23 MA MA050443A patent/MA50443A/fr unknown
- 2018-10-23 CN CN201880082668.1A patent/CN111511359A/zh active Pending
- 2018-10-23 US US16/759,014 patent/US11179363B2/en active Active
- 2018-10-23 PT PT187868237T patent/PT3700513T/pt unknown
Also Published As
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PT3700513T (pt) | 2022-11-30 |
EP3569228A1 (en) | 2019-11-20 |
US11179363B2 (en) | 2021-11-23 |
CN111511359A (zh) | 2020-08-07 |
JP2021509411A (ja) | 2021-03-25 |
EP3700513A2 (en) | 2020-09-02 |
AU2018355698A1 (en) | 2020-05-14 |
MA50443A (fr) | 2020-09-02 |
EP3700513B1 (en) | 2022-08-24 |
BR112020008350A2 (pt) | 2020-11-03 |
US20210177798A1 (en) | 2021-06-17 |
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