BQ-788(BQ-788) - 药物靶点：ETB_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

ETB

作用机制

ETB拮抗剂(内皮素B受体拮抗剂)

治疗领域

心血管疾病肿瘤皮肤和肌肉骨骼疾病

在研适应症-

非在研适应症

高血压黑色素瘤

原研机构

Merck Serono SA

在研机构-

非在研机构

Merck Serono SAMelCure

最高研发阶段终止临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

登录后查看时间轴

结构

分子式C34H51N5O7

InChIKeyLPAHKJMGDSJDRG-DJYQTOCQSA-N

CAS号173326-37-9

关联

8

项与 BQ-788 相关的临床试验

NCT03679780 / Completed临床1期IIT

The Effect of Endothelin and L-Arginine on Racial Differences in Vasoconstriction

The goal of the study is to examine the possible mechanisms of impaired cutaneous microvascular function through local heating along with administration of vasoconstrictors.

开始日期2018-10-01

申办/合作机构

The University of Texas at Arlington

NCT04907838 / Unknown statusN/A

Insulin Stimulated Vasodilation in Patients With Type 2 Diabetes

This study evaluates the role of endothelin in insulin stimulated vasodilation and glucose uptake. The subjects will complete an hyperinsulinemic euglycemic clamp with and without blockade of the endothelin receptors.

开始日期2018-05-01

申办/合作机构

University of Southern Denmark

[+1]

NCT02062346 / CompletedN/AIIT

The Vascular Effects of Endothelin Receptor Antagonism in Systemic Vasculitis

Patients with vasculitis commonly develop cardiovascular disease. The reasons for this are not clear and is not adequately treated with current drugs. It is thus understand the reasons why patients with vasculitis develop cardiovascular disease in order to develop new drugs to reduced this risk.
Endothelin is a chemical produced by blood vessels that contributes to the development of hypertension and cardiovascular disease Higher than normal levels of endothelin are seen in patients with vasculitis but how this contributes to cardiovascular disease in patients with vasculitis is not clear. By using drugs that block the effects of endothelin ('endothelin receptor antagonists') the investigators can hopefully reduce the risk of cardiovascular disease in patients with vasculitis. The purpose of the study is to ascertain if endothelin receptor antagonists improve blood vessel function in patients with vasculitis.

开始日期2016-08-01

申办/合作机构

The University of Edinburgh

[+1]

100 项与 BQ-788 相关的临床结果

登录后查看更多信息

100 项与 BQ-788 相关的转化医学

登录后查看更多信息

100 项与 BQ-788 相关的专利（医药）

登录后查看更多信息

987

项与 BQ-788 相关的文献（医药）

2024-12-31·Blood Pressure

Endothelin-1- and acetylcholine-mediated effects in human and rat vessels: impact of perivascular adipose tissue, diabetes, angiotensin II, and chemerin

Article

作者: Danser, A. H. Jan ; Tan, Lunbo ; Cruz-López, Edwyn O. ; Verdonk, Koen ; Stolk, Daniël G. ; van den Bogaerdt, Antoon J.

OBJECTIVETo study the role of perivascular adipose tissue (PVAT) in the reactivity of rat and human vessels.METHODSIliac and mesenteric arteries were obtained from normotensive Sprague-Dawley rats, hypertensive transgenic (mRen2)27 rats overexpressing mouse renin, and (mRen2)27 rats made diabetic with streptozotocin. Human coronary arteries were obtained from donors. Concentration-response curves were constructed to endothelin-1 and acetylcholine with and without PVAT. The contribution of NO and endothelium-dependent hyperpolarization (EDH) were determined making use of the NO synthase inhibitor L-NAME and the EDH inhibitors apamin + TRAM-34. The endothelin type A and type B (ET_A, ET_B) receptor blockers BQ123 and BQ788, the chemerin inhibitors α-NETA and pravastatin, and the angiotensin receptor blocker losartan were also used.RESULTSIn rat iliac arteries, PVAT diminished endothelin-induced constriction, while the opposite was true in human coronaries. Coronary effects were unaltered by α-NETA, pravastatin, or losartan. ET_B receptor-mediated relaxation in iliac arteries occurred only with PVAT, and BQ123 blocked endothelin-1-induced constriction. Diabetes upregulated the anticontractile effects of PVAT. In rat mesenteric arteries, acetylcholine-induced relaxation with PVAT relied on NO, and on NO + EDH without PVAT. Diabetes upregulated the EDH component exclusively with PVAT.CONCLUSIONPVAT modulates ET-1-induced constriction in a vessel type-dependent manner. Its enhancing effects in coronaries involved neither chemerin nor angiotensin II. Its anticontractile effects in rat iliac arteries involved ET_B receptor-mediated relaxation. Diabetes upregulated PVAT's anticontractile effects. In mesenteric arteries, PVAT counterbalanced the EDH component of the relaxant effect of acetylcholine. Diabetes reversed this effect by upregulating the EDH component.

2024-12-01·Glia

Endothelin‐1 increases Na⁺‐K⁺‐2Cl⁻ cotransporter‐1 expression in cultured astrocytes and in traumatic brain injury model: An involvement of HIF1α activation

Article

作者: Fukui, Yura ; Izumi, Yasuhiko ; Fujimoto, Rina ; Hosogi, Nami ; Hishinuma, Shigeru ; Michinaga, Shotaro ; Koyama, Yutaka ; Ogawa, Yasuhiro ; Takahashi, Kenta ; Hamada, Yasuhiro

AbstractNa+‐K+‐2Cl− cotransporter‐1 (NKCC1) is present in brain cells, including astrocytes. The expression of astrocytic NKCC1 increases in the acute phase of traumatic brain injury (TBI), which induces brain edema. Endothelin‐1 (ET‐1) is a factor that induces brain edema and regulates the expression of several pathology‐related genes in astrocytes. In the present study, we investigated the effect of ET‐1 on NKCC1 expression in astrocytes. ET‐1 (100 nM)‐treated cultured astrocytes showed increased NKCC1 mRNA and protein levels. The effect of ET‐1 on NKCC1 expression in cultured astrocytes was reduced by BQ788 (1 μM), an ETB antagonist, but not by FR139317 (1 μM), an ETA antagonist. The involvement of ET‐1 in NKCC1 expression in TBI was examined using a fluid percussion injury (FPI) mouse model that replicates the pathology of TBI with high reproducibility. Administration of BQ788 (15 nmol/day) decreased FPI‐induced expressions of NKCC1 mRNA and protein, accompanied with a reduction of astrocytic activation. FPI‐induced brain edema was attenuated by BQ788 and NKCC1 inhibitors (azosemide and bumetanide). ET‐1‐treated cultured astrocytes showed increased mRNA and protein expression of hypoxia‐inducible factor‐1α (HIF1α). Immunohistochemical observations of mouse cerebrum after FPI showed co‐localization of HIF1α with GFAP‐positive astrocytes. Increased HIF1α expression in the TBI model was reversed by BQ788. FM19G11 (an HIF inhibitor, 1 μM) and HIF1α siRNA suppressed ET‐induced increase in NKCC1 expression in cultured astrocytes. These results indicate that ET‐1 increases NKCC1 expression in astrocytes through the activation of HIF1α.

2024-11-06·Clinical Science

Complex regulation of tau phosphorylation by the endothelin system in brain microvascular endothelial cells (BMVECs): link to barrier function

Article

作者: Ergul, Adviye ; Jamil, Sarah ; Abdul, Yasir ; Albayram, Onder ; Karakaya, Eda ; Edwards, Jazlyn

AbstractEndothelin-1 (ET-1), the most potent vasoconstrictor identified to date, contributes to cerebrovascular dysfunction. ET-1 levels in postmortem brain specimens from individuals diagnosed with Alzheimer’s disease (AD) and related dementias (ADRD) were shown to be related to cerebral hypoxia and disease severity. ET-1-mediated vascular dysfunction and ensuing cognitive deficits have also been reported in experimental models of AD and ADRD. Moreover, studies also showed that ET-1 secreted from brain microvascular endothelial cells (BMVECs) can affect neurovascular unit integrity in an autocrine and paracrine manner. Vascular contributions to cognitive impairment and dementia (VCID) is a leading ADRD cause known to be free of neuronal tau pathology, a hallmark of AD. However, a recent study reported cytotoxic hyperphosphorylated tau (p-tau) accumulation, which fails to bind or stabilize microtubules in BMVECs in VCID. Thus, the study aimed to determine the impact of ET-1 on tau pathology, microtubule organization, and barrier function in BMVECs. Cells were stimulated with 1 μM ET-1 for 24 h in the presence/absence of ETA (BQ123; 20 μM) or ETB (BQ788; 20 μM) receptor antagonists. Cell lysates were assayed for an array of phosphorylation site-specific antibodies and microtubule organization/stabilization markers. ET-1 stimulation increased p-tau Thr231 but decreased p-tau Ser199, Ser262, Ser396, and Ser214 levels only in the presence of ETA or ETB antagonism. ET-1 also impaired barrier function in the presence of ETA antagonism. These novel findings suggest that (1) dysregulation of endothelial tau phosphorylation may contribute to cerebral microvascular dysfunction and (2) the ET system may be an early intervention target to prevent hyperphosphorylated tau-mediated disruption of BMVEC barrier function.

100 项与 BQ-788 相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
-	BQ-788	-	-

研发状态

10 条进展最快的记录,

登录

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
黑色素瘤	临床2期	-	MelCure	2011-05-01
高血压	临床2期	-	Merck Serono SA	-

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01395329 (NETS, CTgov)	临床4期	高血压 \| 高血压前期	42	FBF response to Sodium Nitroprusside+Nebivolol+ACh+BQ-788+BQ-123 (Nebivolol)	築蓋衊鬱繭壓鏇淵鹽艱(範構蓋鏇鹽願鏇鏇遞膚) = 積獵範廠襯獵簾積衊願壓觸遞淵繭蓋獵積製齋 (鬱齋憲鏇繭襯鹽艱窪糧, 壓衊築築襯繭壓壓鬱鹽 ~ 範衊醖糧餘襯選衊夢糧) 更多	-	2018-12-06
NCT01395329 (NETS, CTgov)	临床4期	高血压 \| 高血压前期	42	FBF response to Sodium Nitroprusside+Metoprolol+ACh+BQ-788+BQ-123 (Metoprolol)	築蓋衊鬱繭壓鏇淵鹽艱(範構蓋鏇鹽願鏇鏇遞膚) = 艱鏇夢鹹淵構觸艱遞遞壓觸遞淵繭蓋獵積製齋 (鬱齋憲鏇繭襯鹽艱窪糧, 簾繭壓築選鹹鬱艱繭淵 ~ 糧願醖鹹艱窪選構鏇築) 更多	-	2018-12-06
NCT02442466 (Pubmed \| Oncologist) 人工标引	临床1期	黑色素瘤	5	BQ788	(構窪鏇簾膚鏇簾艱築鬱) = 淵壓鏇鹽獵淵鏇範艱衊鏇築選構鑰鬱製膚鹽糧 (鏇廠獵鏇鏇構廠餘鹽顧 )	积极	2015-10-01