Delving into the Latest Updates on BQ-123 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [1]

Target

ETA

Mechanism

ETA antagonists(Endothelin receptor type A antagonists)

Therapeutic Areas

Nervous System Diseases

Active Indication

Brain Edema

Inactive Indication

Arrhythmias, CardiacBrain IschemiaDiabetes Complications+ [7]

Originator Organization

Pharmazz, Inc.

Active Organization

Pharmazz, Inc.

Inactive Organization

University of Glasgow

Western Infirmary

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

Structure

Molecular FormulaC31H42N6O7

InChIKeyVYCMAAOURFJIHD-PJNXIOHISA-N

CAS Registry136553-81-6

Gene Sequence

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

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100 Clinical Results associated with BQ-123

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100 Translational Medicine associated with BQ-123

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100 Patents (Medical) associated with BQ-123

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1,706

Literatures (Medical) associated with BQ-123

01 Feb 2024·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Cardiomyocyte-specific deletion of endothelin receptor A (ETA) obliterates cardiac aging through regulation of mitophagy and ferroptosis

Article

Author: Fan, Xiaoping ; Dong, Feng ; Ceylan, Asli F ; Lin, Jie ; Ren, Jun ; Zou, Rongjun ; Zhang, Miao ; Zhang, Yingmei ; Dong, Maolong ; Turdi, Subat ; Wang, Ge ; Peng, Bo ; Shi, Wanting ; Zou, Zengxiao

Advanced aging evokes unfavorable changes in the heart including cardiac remodeling and contractile dysfunction although the underlying mechanism remains elusive. This study was conducted to evaluate the role of endothelin-1 (ET-1) in the pathogenesis of cardiac aging and mechanism involved. Echocardiographic and cardiomyocyte mechanical properties were determined in young (5-6 mo) and aged (26-28 mo) wild-type (WT) and cardiomyocyte-specific ET_A receptor knockout (ET_AKO) mice. GSEA enrichment identified differentially expressed genes associated with mitochondrial respiration, mitochondrial protein processing and mitochondrial depolarization in cardiac aging. Aging elevated plasma levels of ET-1, Ang II and suppressed serum Fe²⁺, evoked cardiac remodeling (hypertrophy and interstitial fibrosis), contractile defects (fractional shortening, ejection fraction, cardiomyocyte peak shortening, maximal velocity of shortening/relengthening and prolonged relengthening) and intracellular Ca²⁺ mishandling (dampened intracellular Ca²⁺ release and prolonged decay), the effects with the exception of plasma AngII, ET-1 and Fe²⁺ were mitigated by ET_AKO. Advanced age facilitated O₂^- production, carbonyl protein damage, cardiac hypertrophy (GATA4, ANP, NFATc3), ER stress, ferroptosis, compromised autophagy (LC3B, Beclin-1, Atg7, Atg5 and p62) and mitophagy (parkin and FUNDC1), and deranged intracellular Ca²⁺ proteins (SERCA2a and phospholamban), the effects of which were reversed by ET_A ablation. ET-1 provoked ferroptosis in vitro, the response was nullified by the ET_A receptor antagonist BQ123 and mitophagy inducer CsA. ET_A but not ET_B receptor antagonism reconciled cardiac aging, which was abrogated by inhibition of mitophagy and ferroptosis. These findings collectively denote promises of targeting ET_A, mitophagy and ferroptosis in the management of aging-associated cardiac remodeling and contractile defect.

01 Oct 2023·International immunopharmacology

Involvement of cannabinoid receptors and neuroinflammation in early sepsis: Implications for posttraumatic stress disorder.

Article

Author: Matias, Maycon Eduardo ; Raymundi, Ana Maria ; Rodrigues da Silva, Thiago ; Radulski, Débora Rasec ; Stern, Cristina Aparecida Jark ; Zampronio, Aleksander Roberto

Sepsis is associated with several comorbidities in survivors, such as posttraumatic stress disorder (PTSD). This study investigated whether rats that survive sepsis develop the generalization of fear memory as a model of PTSD. Responses to interventions that target the endothelin-1 (ET-1)/cannabinoid system and glial activation in the initial stages of sepsis were evaluated. As a control, we evaluated hyperalgesia before fear conditioning. Sepsis was induced by cecal ligation and puncture (CLP) in Wistar rats. CLP-induced sepsis with one or three punctures resulted in fear generalization in the survivors 13 and 20 days after the CLP procedure, a process that was not associated with hyperalgesia. Septic animals were intracerebroventricularly treated with vehicle, the endothelin receptor A (ET_A) antagonist BQ123, the cannabinoid CB₁ and CB₂ receptor antagonists AM251 and AM630, respectively, and the glial blocker minocycline 4 h after CLP. The blockade of either CB₁ or ET_A receptors increased the survival rate, but only the former reversed fear memory generalization. The endothelinergic system blockade is important for improving survival but not for fear memory. Treatment with the CB₂ receptor antagonist or minocycline also reversed the generalization of fear memory but did not increase the survival rate that was associated with CLP. Minocycline treatment also reduced tumor necrosis factor-α levels in the hippocampus suggesting that neuroinflammation is important for the generalization of fear memory induced by CLP. The influence of CLP on the generalization of fear memory was not related to Arc protein expression, a regulator of synaptic plasticity, in the dorsal hippocampus.

01 Sep 2023·International ophthalmology

The effect of ET1-CTGF mediated pathway on the accumulation of extracellular matrix in the trabecular meshwork and its contribution to the increase in IOP.

Article

Author: Guo, Jingmin ; Liu, Ying ; Rong, Yan ; Wang, Ping ; Chen, Wei ; Deng, Chaohua ; Manyande, Anne ; Chen, Zhiqi ; Zhang, Hong ; Zhu, Mengxia ; Xiang, Yan ; Wang, Junming

PURPOSETo investigate the effect of endothelin-1 (ET-1) in excessive accumulation of extracellular matrix (ECM) of the trabecular meshwork (TM) and its role in intraocular pressure (IOP) regulation.METHODSCultured human TM cells (HTMCs) were treated with ET-1, ET-1 + ETA receptor (ETAR) antagonist BQ123, ET-1 + ETB receptor (ETBR) antagonist BQ788. The expressions of fibronectin (FN) and collagen type IV (Col IV) were evaluated by western blotting and immunofluorescence. A time course effect of ET-1 on the transcription level of connective tissue growth factor (CTGF) was investigated by qRT-PCR. Next, the transcription level of CTGF was downregulated by using antisense oligodeoxynucleotide sequence. Then HTMCs were treated with ET-1, and the expression levels of FN and Col IV were evaluated by western blotting. In addition, by using an ex-vivo model of cultured anterior eye segment, we explored the effect of ET-1 on IOP changes and the expressions of FN and Col IV.RESULTSIn cultured HTMCs, the expressions of FN and Col IV were significantly increased after ET-1 treatment, which were blocked by the pretreatment of ETAR antagonist BQ123, rather than ETBR antagonist BQ788. Besides, the CTGF mRNA level increased significantly and reached a peak after 48 h of ET-1 treatment. However, the effect of ET-1 on increasing the expressions of FN and Col IV in HTMCs could be inhibited by the downregulation of CTGF. In an ex-vivo model, IOP increased significantly after ET-1 administration, which could be blocked by BQ123 but not by BQ788. Furthermore, elevated expressions of FN and Col IV in TM were observed after ET-1 perfusion, and could be inhibited by BQ123 pretreatment.CONCLUSIONExcessive ET-1 in aqueous humor could lead to the abnormal accumulation of FN and Col IV in TM via the ETA-CTGF pathway, thereby increasing IOP.

100 Deals associated with BQ-123

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External Link

KEGG	Wiki	ATC	Drug Bank
-	BQ-123	-	DB12054

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Brain Edema	Phase 2	-	Pharmazz, Inc.	-
Heart Failure	Phase 2	GB	University of Glasgow	-
Hypertension, Pregnancy-Induced	Phase 2	US	-	-
Ulcer	Phase 2	JP	-	-
Arrhythmias, Cardiac	Preclinical	GB	Western Infirmary	-
Brain Ischemia	Preclinical	US	-	-
Diabetes Complications	Preclinical	JP	-	-
Hypertension	Preclinical	JP	-	-
Peripheral Vascular Diseases	Preclinical	JP	-	-
Diabetic Ketoacidosis	Discovery	US	Pharmazz, Inc.	10 Sep 2016

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04907838 (Pubmed \| Gen Comp Endocrinol)	Not Applicable	Diabetes Mellitus, Type 2 ET-1	-	BQ-123	zcwalccnpu(ovkofxetin) = jglahfwxyx kmaazusbvh (uxlypqsjti, %change)	-	01 Mar 2022
NCT00586820 (CTgov)	Phase 2	Myocardial Reperfusion Injury \| Non-St Elevated Myocardial Infarction \| Microvascular Disease	23	BQ-123 (BQ-123)	whuuaikfam(xdllitlkpa) = bjzhwrypom jsszerhgpx (wxqdokndch, kmsxsppovk - avbjftqdap) View more	-	04 Jul 2014
NCT00586820 (CTgov)	Phase 2		23	Placebo (Placebo)	whuuaikfam(xdllitlkpa) = fnvjggelja jsszerhgpx (wxqdokndch, mkyeskzrkz - lsztklowoo) View more	-	04 Jul 2014
NCT00759408 (CTgov)	Phase 2	Hypertension, Pulmonary	38	BQ-123	yymbqezkok(wvoimirers) = rmqwztkuok dlccrbhwvx (mqohtrniou, xzjoylxlqy - zcvdzfbnsm) View more	-	24 Oct 2018
EULAR2007	Not Applicable	Scleroderma, Systemic	12	BQ-123	wyodhqudra(bqmcpmkokf) = ybgslsnbmp tkfbrdzrlt (jfismhobgf, 3.9)	-	13 Jun 2007
EULAR2007	Not Applicable	Scleroderma, Systemic	12	Saline	wyodhqudra(bqmcpmkokf) = mbxqwdinsr tkfbrdzrlt (jfismhobgf, 1.6)	-	13 Jun 2007
NCT02124824 (CTgov)	Early Phase 1	Hydrops Fetalis \| Heart Failure	30	BQ-123 (Arm 1: Control)	qpbyuhcefw(nbbrytqwuh) = gcvfdjzomy snjuyooovu (seumrcsmop, usnyclnaqf - gulaxktkoh) View more	-	20 Dec 2021
NCT02124824 (CTgov)	Early Phase 1	Hydrops Fetalis \| Heart Failure	30	BQ-123 (Arm 2: Heart Failure)	qpbyuhcefw(nbbrytqwuh) = ifhjhobftd snjuyooovu (seumrcsmop, nxlteomwwz - ybzxydnumg) View more	-	20 Dec 2021
ISC2023	Not Applicable	-	-	Intranasal BQ-123	wmisvjzmqw(ykvrlwkebb) = kacrcfvvck kcljgplmdx (vknsqkvaxn )	-	01 Feb 2023