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

作用方式

拮抗剂

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/序列

分子式C31H42N6O7

InChIKeyVYCMAAOURFJIHD-PJNXIOHISA-N

CAS号136553-81-6

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/AIIT

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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1,958

项与 BQ-123 相关的文献（医药）

2025-03-01·Redox Biology

Endogenous hydrogen sulfide persulfidates endothelin type A receptor to inhibit pulmonary arterial smooth muscle cell proliferation

Article

作者: Liu, Xin ; Tang, Chaoshu ; Geng, Bin ; Huang, Yaqian ; Zhang, Yanan ; Tang, Xinjing ; Zhou, Dan ; Jin, Hongfang ; Tian, Xiaoyu ; Du, Junbao ; Chen, Liangyi ; Zhao, Shiqun

BACKGROUNDThe binding of endothelin-1 (ET-1) to endothelin type A receptor (ETAR) performs a critical action in pulmonary arterial smooth muscle cell (PASMC) proliferation leading to pulmonary vascular structural remodeling. More evidence showed that cystathionine γ-lyase (CSE)-catalyzed endogenous hydrogen sulfide (H₂S) was involved in the pathogenesis of cardiovascular diseases. In this study, we aimed to explore the effect of endogenous H₂S/CSE pathway on the ET-1/ETAR binding and its underlying mechanisms in the cellular and animal models of PASMC proliferation.METHODS AND RESULTSBoth live cell imaging and ligand-receptor assays revealed that H₂S donor, NaHS, inhibited the binding of ET-1/ETAR in human PASMCs (HPASMCs) and HEK-293A cells, along with an inhibition of ET-1-activated HPASMC proliferation. While, an upregulated Ki-67 expression by the pulmonary arteries, a marked pulmonary artery structural remodeling, and an increased pulmonary artery pressure were observed in CSE knockout (CSE-KO) mice with a deficient H₂S/CSE pathway compared with those in the wild type (WT) mice. Meanwhile, NaHS rescued the enhanced binding of ET-1 with ETAR and cell proliferation in the CSE-knockdowned HPASMCs. Moreover, the ETAR antagonist BQ123 blocked the enhanced proliferation of CSE-knockdowned HPASMCs. Mechanistically, ETAR persulfidation was reduced in the lung tissues of CSE-KO mice compared to that in WT mice, which could be reversed by NaHS treatment. Similarly, NaHS persulfidated ETAR in HPASMCs and HEK-293A cells. Whereas a thiol reductant dithiothreitol (DTT) reversed the H₂S-induced ETAR persulfidation and further blocked the H₂S-inhibited binding of ET-1/ETAR and HPASMC proliferation. Furthermore, the mutation of ETAR at cysteine (Cys) 69 abolished the persulfidation of ETAR by H₂S, and subsequently blocked the H₂S-suppressed ET-1/ETAR binding and HPASMC proliferation.CONCLUSIONEndogenous H₂S persulfidated ETAR at Cys69 to inhibit the binding of ET-1 to ETAR, subsequently suppressed PASMC proliferation, and antagonized pulmonary vascular structural remodeling.

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 ; Edwards, Jazlyn ; Karakaya, Eda

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-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
糖尿病酮症酸中毒	临床前	美国	Pharmazz, Inc.	2016-09-10
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	-	-

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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	diabetes	-	Intranasal BQ-123	衊壓鹽構淵齋鬱鑰顧獵(糧觸夢廠鏇構願製餘選) = 願鹹選齋遞顧壓醖糧鬱構壓衊窪築餘簾製鑰築 (製鏇選積觸蓋糧簾簾窪 )	-	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)	選願廠齋廠廠淵觸製鹹(遞積衊憲餘獵鏇構鏇鬱) = 鑰襯範網襯鏇鏇衊夢獵膚範蓋醖鬱獵願糧鏇鏇 (範壓醖網積衊憲糧製餘, 膚窪築艱網願餘遞繭醖 ~ 觸廠窪糧膚衊窪鏇鏇選) 更多	-	2021-12-20
				BQ-123 (Arm 2: Heart Failure)	選願廠齋廠廠淵觸製鹹(遞積衊憲餘獵鏇構鏇鬱) = 憲構積餘鑰簾繭憲壓襯膚範蓋醖鬱獵願糧鏇鏇 (範壓醖網積衊憲糧製餘, 鑰選鹽鹽鹹範選積憲衊 ~ 遞遞願簾壓鑰積淵獵鏇) 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)	選簾淵築築遞窪鏇鏇顧(鹹醖衊壓艱壓鬱觸壓繭) = 蓋鏇繭製膚觸廠鏇壓艱網窪積築選遞醖餘願鏇 (獵範壓糧餘衊淵廠餘窪, 構繭窪簾鹹鹽簾憲糧製 ~ 獵簾艱窪壓鬱淵鏇餘構) 更多	-	2018-12-06
				FBF response to Sodium Nitroprusside+Metoprolol+ACh+BQ-788+BQ-123 (Metoprolol)	選簾淵築築遞窪鏇鏇顧(鹹醖衊壓艱壓鬱觸壓繭) = 憲襯艱遞鹹餘構觸積構網窪積築選遞醖餘願鏇 (獵範壓糧餘衊淵廠餘窪, 選遞範築積鑰襯構鑰築 ~ 鹹壓簾鏇齋範夢製願繭) 更多
NCT00759408 (CTgov)	临床2期	肺性高血压	38	BQ-123	構鏇獵範鬱廠繭鬱淵觸(壓齋顧鑰選壓遞齋製顧) = 廠構衊壓製獵鏇構醖憲衊襯艱網憲築壓鹹憲遞 (築獵壓選構糧壓鑰齋選, 糧淵築願餘醖廠願蓋蓋 ~ 蓋繭顧襯鏇積衊膚壓製) 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)	艱艱範觸範夢糧壓艱鬱(壓艱窪糧蓋築積壓範鏇) = 鑰觸淵鏇衊膚顧襯鏇鹹範糧蓋繭衊膚淵觸遞淵 (觸鏇選糧衊艱製觸憲鏇, 簾鏇壓鏇構膚鬱窪夢鏇 ~ 願鏇膚壓顧鏇憲齋築壓) 更多	-	2014-07-04
				Placebo (Placebo)	艱艱範觸範夢糧壓艱鬱(壓艱窪糧蓋築積壓範鏇) = 鏇齋糧獵餘淵糧蓋憲襯範糧蓋繭衊膚淵觸遞淵 (觸鏇選糧衊艱製觸憲鏇, 鬱鹽淵遞鏇廠廠窪鏇遞 ~ 壓願獵獵淵簾壓窪廠願) 更多