BQ-123(BQ-123) - 药物靶点：ETA_在研适应症：脑水肿_专利_临床

概要

基本信息

药物类型

小分子化药

别名

+ [1]

靶点

ETA

作用机制

ETA拮抗剂(内皮素A受体拮抗剂)

治疗领域

在研适应症

非在研适应症

原研机构

在研机构

非在研机构

University of Glasgow

Western Infirmary

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C31H42N6O7

InChIKeyVYCMAAOURFJIHD-PJNXIOHISA-N

CAS号136553-81-6

序列信息

Sequence Code 15188913

关联

17

项与 BQ-123 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]

NCT02987465 / CompletedN/AIIT

An Observational, Open-label Pilot Study to Evaluate the Effect of Standard-of-care Erythropoiesis-stimulating Agents (Darbepoetin Alfa) on Forearm Blood Flow in Nondialysis-dependent Subjects With Anaemia Associated With Chronic Kidney Disease.

In people diagnosed with chronic kidney disease (CKD) anaemia is a common problem and is often treated with EPO (Erythropoietin). One form of EPO used is Darbepoetin (Aranesp®). EPO is safe to use but it has been associated with a rise in blood pressure (BP) in some individuals. The reasons for this are not clear. To try to explain this, this study will look at how EPO affects certain substances in the blood that influence how blood vessels contract and relax. This will be conducted by infusing small amounts of Acetylcholine, BQ123 and Noradrenaline into the arm vessels of volunteers using an established method called Forearm blood flow (plethysmography). Volunteers recruited for this study will include CKD patients undergoing therapy with Darbepoetin as part of their normal NHS care as well as healthy people not on treatment, who will act as controls. This is an observational pilot study of changes in physiology before and after Darbepoetin. It will provide valuable data for a later study comparing Darbepoetin to novel agents which work via different pathways to treat anaemia.

开始日期2017-02-20

申办/合作机构

Cambridge University Hospitals NHS Foundation Trust

[+1]

100 项与 BQ-123 相关的临床结果

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100 项与 BQ-123 相关的转化医学

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100 项与 BQ-123 相关的专利（医药）

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1,706

项与 BQ-123 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.

2024-11-06·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.

2024-08-21·Clinical Science

Endothelin-1 (ET-1) contributes to senescence and phenotypic changes in brain pericytes in diabetes-mimicking conditions

Article

作者: Ergul, Adviye ; Abdul, Yasir ; Jamil, Sarah ; Edgerton-Fulton, Mia

AbstractDiabetes mediates endothelial dysfunction and increases the risk of Alzheimer’s disease and related dementias. Diabetes also dysregulates the ET system. ET-1-mediated constriction of brain microvascular pericytes (BMVPCs) has been shown to contribute to brain hypoperfusion. Cellular senescence, a process that arrests the proliferation of harmful cells and instigates phenotypical changes and proinflammatory responses in endothelial cells that impact their survival and function. Thus, we hypothesized that ET-1 mediates BMVPC senescence and phenotypical changes in diabetes-like conditions. Human BMVPCs were incubated in diabetes-like conditions with or without ET-1 (1 µmol/L) for 3 and 7 days. Hydrogen peroxide (100 µmol/L H2O2) was used as a positive control for senescence and to mimic ischemic conditions. Cells were stained for senescence-associated β-galactosidase or processed for immunoblotting and quantitative real-time PCR analyses. In additional experiments, cells were stimulated with ET-1 in the presence or absence of ETA receptor antagonist BQ-123 (20 μmol/L) or ETB receptor antagonist BQ-788 (20 μmol/L). ET-1 stimulation increased β-galactosidase accumulation which was prevented by BQ-123. ET-1 also increased traditional senescence marker p16 protein and pericyte-specific senescence markers, TGFB1i1, PP1CA, and IGFBP7. Furthermore, ET-1 stimulated contractile protein α-SMA and microglial marker ostepontin in high glucose suggesting a shift toward an ensheathing or microglia-like phenotype. In conclusion, ET-1 triggers senescence, alters ETA and ETB receptors, and causes phenotypical changes in BMVPCs under diabetes-like conditions. These in vitro findings need to be further studied in vivo to establish the role of ETA receptors in the progression of pericyte senescence and phenotypical changes in VCID.

100 项与 BQ-123 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	BQ-123	-	DB12054

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
脑水肿	临床2期	-	Pharmazz, Inc.	-
疼痛	临床前	美国	Pharmazz, Inc.	2017-10-18
心律失常	临床前	英国	Western Infirmary	-
脑缺血	临床前	美国	-	-
心脏衰竭	临床前	英国	University of Glasgow	-
高血压	临床前	日本	-	-
妊娠期高血压	临床前	美国	-	-
外周血管疾病	临床前	日本	-	-
溃疡	临床前	日本	-	-
糖尿病酮症酸中毒	药物发现	美国	Pharmazz, Inc.	2016-09-10

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ISC2023	N/A	-	-	Intranasal BQ-123	憲餘範鏇構鹽製構繭獵(淵窪範顧構廠構鏇鏇鹹) = 觸餘壓齋淵艱憲襯願觸壓獵選鑰醖壓網鑰選憲 (鑰衊觸窪衊繭觸齋廠蓋 )	-	2023-02-01
NCT02124824 (CTgov)	早期临床1期	胎儿水肿 \| 心脏衰竭	30	BQ-123 (Arm 1: Control)	選觸憲齋蓋鑰鹹鏇壓觸(壓襯選鹽遞築廠齋簾襯) = 窪糧餘齋糧選膚鹽獵鬱網淵鬱壓簾蓋窪遞鬱壓 (餘鬱繭願齋淵艱餘遞範, 願獵獵網願淵廠鑰構廠 ~ 憲糧膚衊遞糧製鬱壓選) 更多	-	2021-12-20
				BQ-123 (Arm 2: Heart Failure)	選觸憲齋蓋鑰鹹鏇壓觸(壓襯選鹽遞築廠齋簾襯) = 膚鑰襯淵範窪積選膚遞網淵鬱壓簾蓋窪遞鬱壓 (餘鬱繭願齋淵艱餘遞範, 觸鏇憲鏇膚鏇選糧鹹淵 ~ 夢糧選網構鬱遞製夢構) 更多
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)	網鹹鬱膚獵蓋糧範醖積(餘憲鹹顧壓壓選範製繭) = 範網網遞觸網糧積窪壓憲壓餘範獵膚窪衊遞鬱 (憲憲壓顧襯壓願艱範顧, 廠遞製壓觸積顧繭窪餘 ~ 網齋繭選網襯醖觸積淵) 更多	-	2018-12-06
				FBF response to Sodium Nitroprusside+Metoprolol+ACh+BQ-788+BQ-123 (Metoprolol)	網鹹鬱膚獵蓋糧範醖積(餘憲鹹顧壓壓選範製繭) = 淵蓋蓋遞鏇醖餘鏇憲遞憲壓餘範獵膚窪衊遞鬱 (憲憲壓顧襯壓願艱範顧, 夢鑰襯齋鹹壓衊膚遞窪 ~ 範蓋製糧鬱觸鹹窪壓鏇) 更多
NCT00759408 (CTgov)	临床2期	肺性高血压	38	BQ-123	衊獵觸衊襯選襯蓋製醖(選築範艱襯鹹餘網顧壓) = 鹹鏇憲構艱範範製蓋築鹹淵鏇艱餘醖構製繭遞 (廠鏇獵鹽艱鏇網艱鏇壓, 繭膚願鑰蓋鏇壓觸繭鹹 ~ 鬱廠艱憲夢餘遞選選衊) 更多	-	2018-10-24
NCT00586820 (BQ-123, CTgov)	临床2期	心肌再灌注损伤 \| 微血管疾病 \| 非ST段抬高型心肌梗死	23	BQ-123 (BQ-123)	觸鬱憲襯醖蓋淵獵憲鹽(淵顧鹽膚範鏇築襯膚觸) = 齋襯網範積簾顧簾選顧構襯鑰鬱膚鏇膚窪餘鹽 (簾構憲鬱鑰淵淵製鹹齋, 醖簾餘繭鑰齋遞鹽選窪 ~ 觸鏇窪膚鹹鑰築膚鬱鑰) 更多	-	2014-07-04
				Placebo (Placebo)	觸鬱憲襯醖蓋淵獵憲鹽(淵顧鹽膚範鏇築襯膚觸) = 襯築願繭壓衊齋選齋願構襯鑰鬱膚鏇膚窪餘鹽 (簾構憲鬱鑰淵淵製鹹齋, 鏇簾廠構繭壓齋簾憲獵 ~ 鑰積遞鬱廠繭淵夢淵鹽) 更多