Danegaptide
(Synonyms: (2S,4R)-1-(2-氨基乙酰基)-4-苯甲酰胺吡咯烷-2-甲酸,GAP-134; ZP 1609) 目录号 : GC35806
Danegaptide (GAP-134) 是修饰的二肽，是第二代口服生物相容性的间隙连接调节剂。
Cas No.:943134-39-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Danegaptide (GAP-134), a small modified dipeptide, has been identified as a potent and selective second generation gap junction modifier with oral bioavailability. Gap junction.
Gap junction uncoupling can alter conduction pathways and promote cardiac re-entry mechanisms that potentiate many supraventricular arrhythmias, such as atrial fibrillation (AF) and atrial flutter (AFL). Gap junction modifier Danegaptide (GAP-134), showed consistent efficacy on measures of conduction and AF/AFL inducibility in the canine sterile pericarditis model. Danegaptide (GAP-134) is a pharmalogical agent with a favorable clinical safety profile and potential antiarrhythmic efficacy, as already confirmed in phase I clinical trials.
[1]. De Vuyst E, Boengler K, Antoons G, et al. Pharmacological modulation of connexin-formed channels in cardiac pathophysiology. Br J Pharmacol. 2011 Jun;163(3):469-83. [2]. Laurent G, Leong-Poi H, Mangat I, et al. Effects of chronic gap junction conduction-enhancing antiarrhythmic peptide GAP-134 administration on experimental atrial fibrillation in dogs. Circ Arrhythm Electrophysiol. 2009 Apr;2(2):171-8. [3]. Hennan JK, Swillo RE, Morgan GA, et al. GAP-134 ([2S,4R]-1-[2-aminoacetyl]4-benzamidopyrrolidine-2-carboxylic acid) prevents spontaneous ventricular arrhythmias and reduces infarct size during myocardial ischemia/reperfusion injury in open-chest dogs. J Cardiovasc Pharmacol Ther. 2009 Sep;14(3):207-14. [4]. Rossman EI, Liu K, Morgan GA, et al. The gap junction modifier, GAP-134 [(2S,4R)-1-(2-aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic acid], improves conduction and reduces atrial fibrillation/flutter in the canine sterile pericarditis model. J Pharmacol Exp Ther. 2009 Jun;329(3):1127-33. [5]. Eugene L. Piatnitski Cheklera, John A. Buterab, Li Dib, Discovery of a class of potent gap-junction modifiers as novel antiarrhythmic agents. Bioorganic & Medicinal Chemistry Letters. 2009,19(16): 4551-4554
| Cas No. | 943134-39-2 | SDF | |
| 别名 | (2S,4R)-1-(2-氨基乙酰基)-4-苯甲酰胺吡咯烷-2-甲酸,GAP-134; ZP 1609 | ||
| Canonical SMILES | O=C(N[C@H]1CN(C(CN)=O)[C@H](C(O)=O)C1)C2=CC=CC=C2 | ||
| 分子式 | C14H17N3O4 | 分子量 | 291.3 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.4329 mL | 17.1644 mL | 34.3289 mL |
| 5 mM | 0.6866 mL | 3.4329 mL | 6.8658 mL |
| 10 mM | 0.3433 mL | 1.7164 mL | 3.4329 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Danegaptide Prevents TGFβ1-Induced Damage in Human Proximal Tubule Epithelial Cells of the Kidney
Int J Mol Sci 2021 Mar 10;22(6):2809.PMID:33802083DOI:10.3390/ijms22062809.
Chronic kidney disease (CKD) is a global health problem associated with a number of comorbidities. Recent evidence implicates increased hemichannel-mediated release of adenosine triphosphate (ATP) in the progression of tubulointerstitial fibrosis, the main underlying pathology of CKD. Here, we evaluate the effect of Danegaptide on blocking hemichannel-mediated changes in the expression and function of proteins associated with disease progression in tubular epithelial kidney cells. Primary human proximal tubule epithelial cells (hPTECs) were treated with the beta1 isoform of the pro-fibrotic cytokine transforming growth factor (TGFβ1) ± Danegaptide. qRT-PCR and immunoblotting confirmed mRNA and protein expression, whilst a cytokine antibody array assessed the expression/secretion of proinflammatory and profibrotic cytokines. Carboxyfluorescein dye uptake and ATP biosensing measured hemichannel activity and ATP release, whilst transepithelial electrical resistance was used to assess paracellular permeability. Danegaptide negated carboxyfluorescein dye uptake and ATP release and protected against protein changes associated with tubular injury. Blocking Cx43-mediated ATP release was paralleled by partial restoration of the expression of cell cycle inhibitors, adherens and tight junction proteins and decreased paracellular permeability. Furthermore, Danegaptide inhibited TGFβ1-induced changes in the expression and secretion of key adipokines, cytokines, chemokines, growth factors and interleukins. The data suggest that as a gap junction modulator and hemichannel blocker, Danegaptide has potential in the future treatment of CKD.
Danegaptide Enhances Astrocyte Gap Junctional Coupling and Reduces Ischemic Reperfusion Brain Injury in Mice
Biomolecules 2020 Feb 26;10(3):353.PMID:32110860DOI:10.3390/biom10030353.
Ischemic stroke is a complex and devastating event characterized by cell death resulting from a transient or permanent arterial occlusion. Astrocytic connexin43 (Cx43) gap junction (GJ) proteins have been reported to impact neuronal survival in ischemic conditions. Consequently, Cx43 could be a potential target for therapeutic approaches to stroke. We examined the effect of Danegaptide (ZP1609), an antiarrhythmic dipeptide that specifically enhances GJ conductance, in two different rodent stroke models. In this study, Danegaptide increased astrocytic Cx43 coupling with no significant effects on Cx43 hemichannel activity, in vitro. Using matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI IMS) the presence of Danegaptide within brain tissue sections were detected one hour after reperfusion indicating successful transport of the dipeptide across the blood brain barrier. Furthermore, administration of Danegaptide in a novel mouse brain ischemia/reperfusion model showed significant decrease in infarct volume. Taken together, this study provides evidence for the therapeutic potential of Danegaptide in ischemia/reperfusion stroke.
Danegaptide for primary percutaneous coronary intervention in acute myocardial infarction patients: a phase 2 randomised clinical trial
Heart 2018 Oct;104(19):1593-1599.PMID:29602883DOI:10.1136/heartjnl-2017-312774.
Objectives: Reperfusion immediately after reopening of the infarct-related artery in ST-segment elevation myocardial infarction (STEMI) may cause myocardial damage in addition to the ischaemic insult (reperfusion injury). The gap junction modulating peptide Danegaptide has in animal models reduced this injury. We evaluated the effect of Danegaptide on myocardial salvage in patients with STEMI. Methods: In addition to primary percutaneous coronary intervention in STEMI patients with thrombolysis in myocardial infarction flow 0-1, single vessel disease and ischaemia time less than 6 hours, we tested, in a clinical proof-of-concept study, the therapeutic potential of Danegaptide at two-dose levels. Primary outcome was myocardial salvage evaluated by cardiac MRI after 3 months. Results: From November 2013 to August 2015, a total of 585 patients were randomly enrolled in the trial. Imaging criteria were fulfilled for 79 (high dose), 80 (low dose) and 84 (placebo) patients eligible for the per-protocol analysis. Danegaptide did not affect the myocardial salvage index (Danegaptide high (63.9±14.9), Danegaptide low (65.6±15.6) and control (66.7±11.7), P=0.40), final infarct size (Danegaptide high (19.6±11.4 g), Danegaptide low (18.6±9.6 g) and control (21.4±15.0 g), P=0.88) or left ventricular ejection fraction (Danegaptide high (53.9%±9.5%), Danegaptide low (52.7%±10.3%) and control (52.1%±10.9%), P=0.64). There was no difference between groups with regard to clinical outcome. Conclusions: Administration of Danegaptide to patients with STEMI did not improve myocardial salvage. Trial registration number: NCT01977755; Pre-results.
ZP1609/Danegaptide and mitochondrial connexin hemichannels: a harbinger for peptide drug design
Br J Pharmacol 2017 Aug;174(15):2606-2607.PMID:28567717DOI:10.1111/bph.13891.
This article is a Commentary on Boengler K, Bulic M, Schreckenberg R, Schlüter K-D, Schulz R (2017). The gap junction modifier ZP1609 decreases cardiomyocyte hypercontracture following ischaemia/reperfusion independent from mitochondrial connexin 43. Br J Pharmacol 174: 2060-2073. https://doi.org/10.1111/bph.13804.
Testing Danegaptide Effects on Kidney Function after Ischemia/Reperfusion Injury in a New Porcine Two Week Model
PLoS One 2016 Oct 19;11(10):e0164109.PMID:27760220DOI:10.1371/journal.pone.0164109.
Introduction: Ischemia/reperfusion injury (I/R-I) is a leading cause of acute kidney injury (AKI) and is associated with increased mortality. Danegaptide is a selective modifier of the gap junction protein connexion 43. It has cytoprotective as well as anti-arrhythmic properties and has been shown to reduce the size of myocardial infarct in pigs. The aim of this study was to investigate the ischemia-protective effect of Danegaptide in a porcine renal I/R-I model with two weeks follow up. Methods: Unilateral renal I/R-I was induced in pigs by clamping the left renal artery over a two hour period. The model allowed examination of renal blood flow by magnetic resonance imaging (MRI) and the measurement of single kidney GFR two weeks after injury. Eleven animals were randomized to Danegaptide-infusion while nine animals received placebo. Kidney histology and urinary neutrophil gelatinase-associated lipocalin (NGAL) excretion were included as markers of AKI. Results: Unilateral kidney I/R-I resulted in an immediate ~50% GFR reduction, associated with a four-fold increase in urinary NGAL-excretion. Fourteen days after I/R-I, the total GFR was ~75% of baseline with a significantly lower GFR in the injured left kidney compared to the right kidney. No differences in GFR were observed between the treated and non-treated animals immediately after I/R-I or at Day 14. Furthermore, no differences were observed in the urinary excretion of NGAL, renal blood flow or other markers of renal function. Conclusions: As expected this porcine renal I/R-I model was associated with reduced GFR two weeks after injury. Danegaptide did not improve renal function after I/R-I.