Delving into the Latest Updates on BQ-123 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [1]

Target

ETA

Action

antagonists

Mechanism

ETA antagonists(Endothelin receptor type A antagonists)

Therapeutic Areas

Nervous System Diseases

Active Indication

Brain Edema

Inactive Indication

Arrhythmias, CardiacBrain IschemiaDiabetic Ketoacidosis+ [6]

Originator Organization

Pharmazz, Inc.

Active Organization

Pharmazz, Inc.

Inactive Organization

University of Glasgow

Western Infirmary

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

Login to view timeline

Structure/Sequence

Molecular FormulaC31H42N6O7

InChIKeyVYCMAAOURFJIHD-PJNXIOHISA-N

CAS Registry136553-81-6

Sequence Code 15188913

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.

Start Date20 Feb 2017

Sponsor / Collaborator

Cambridge University Hospitals NHS Foundation Trust

[+1]

100 Clinical Results associated with BQ-123

Login to view more data

100 Translational Medicine associated with BQ-123

Login to view more data

100 Patents (Medical) associated with BQ-123

Login to view more data

1,958

Literatures (Medical) associated with BQ-123

01 Mar 2025·Redox Biology

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

Article

Author: 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.

31 Dec 2024·Blood Pressure

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

Article

Author: 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.

06 Nov 2024·Clinical Science

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

Article

Author: 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 Deals associated with BQ-123

Login to view more data

External Link

KEGG	Wiki	ATC	Drug Bank
-	BQ-123	-	DB12054

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Brain Edema	Phase 2	-	Pharmazz, Inc.	-
Pain	Preclinical	United States	Pharmazz, Inc.	18 Oct 2017
Diabetic Ketoacidosis	Preclinical	United States	Pharmazz, Inc.	10 Sep 2016
Arrhythmias, Cardiac	Preclinical	United Kingdom	Western Infirmary	-
Brain Ischemia	Preclinical	United States	-	-
Heart Failure	Preclinical	United Kingdom	University of Glasgow	-
Hypertension	Preclinical	Japan	-	-
Hypertension, Pregnancy-Induced	Preclinical	United States	-	-
Peripheral Vascular Diseases	Preclinical	Japan	-	-
Ulcer	Preclinical	Japan	-	-

Login to view more data

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ISC2023	Not Applicable	diabetes	-	Intranasal BQ-123	yobxdurhhk(ijbpxixrfr) = orotrnumeu watqpboepb (tteshlggdk )	-	01 Feb 2023
NCT02124824 (CTgov)	Early Phase 1	Hydrops Fetalis \| Heart Failure	30	BQ-123 (Arm 1: Control)	jxggbiiuos(rmectpiabk) = xyypbhqadn vwdbxmzfse (cwojhqpbmc, jfzmxtzvtd - huxnoqgigk) View more	-	20 Dec 2021
				BQ-123 (Arm 2: Heart Failure)	jxggbiiuos(rmectpiabk) = hfdmfbeilh vwdbxmzfse (cwojhqpbmc, surhhncher - hqgprswmde) View more
NCT01395329 (NETS, CTgov)	Phase 4	Hypertension \| Prehypertension	42	FBF response to Sodium Nitroprusside+Nebivolol+ACh+BQ-788+BQ-123 (Nebivolol)	ejxlijgouz(iygnxamujn) = evcxaenhpx guibuqmisy (rgxcacetzm, jnphrdjtyi - lybyzydtza) View more	-	06 Dec 2018
				FBF response to Sodium Nitroprusside+Metoprolol+ACh+BQ-788+BQ-123 (Metoprolol)	ejxlijgouz(iygnxamujn) = xgsykkoyon guibuqmisy (rgxcacetzm, fwteufmvwf - wfijlgndht) View more
NCT00759408 (CTgov)	Phase 2	Hypertension, Pulmonary	38	BQ-123	vdwszdastk(scqfnkmjli) = suielqalgk odrcrixvxt (syydaytrhv, rwarduneum - ispaauueew) View more	-	24 Oct 2018
NCT00586820 (BQ-123, CTgov)	Phase 2	Myocardial Reperfusion Injury \| Microvascular Disease \| Non-St Elevated Myocardial Infarction	23	BQ-123 (BQ-123)	oahgyckelv(kiwbsmasds) = kztlrdboan idqyjprqnw (wlahldtjtb, eenfzelidg - udlzfriuoq) View more	-	04 Jul 2014
				Placebo (Placebo)	oahgyckelv(kiwbsmasds) = qzxodfegdu idqyjprqnw (wlahldtjtb, quzkibjivk - uiivfkutdk) View more