Runcaciguat
(Synonyms: BAY 1101042) 目录号 : GC65192
Runcaciguat 是一种可口服的可溶性鸟甘酸环化酶 soluble guanylate cyclase 促进剂，可结合选择性的部分 adenosine A1 受体激动剂用于研究心血管及肾病。
Cas No.:1402936-61-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Runcaciguat is an orally active stimulator of soluble guanylate cyclase, and is used in the research of cardiovascular and renal diseases combined with selective partial adenosine A1 receptor agonists[1].
[1]. Barbara ALBRECHT-KÜPPER, et al. Selective partial adenosine a1 receptor agonists in combination with soluble guanylyl cyclase (sgc) stimulators and/or activators. WO2018153899A1.
| Cas No. | 1402936-61-1 | SDF | Download SDF |
| 别名 | BAY 1101042 | ||
| 分子式 | C23H22Cl2F3NO3 | 分子量 | 488.33 |
| 溶解度 | DMSO : 125 mg/mL (255.97 mM; Need ultrasonic) | 储存条件 | 4°C, protect from light |
| 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 | 2.0478 mL | 10.239 mL | 20.478 mL |
| 5 mM | 0.4096 mL | 2.0478 mL | 4.0956 mL |
| 10 mM | 0.2048 mL | 1.0239 mL | 2.0478 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。
Runcaciguat, a novel soluble guanylate cyclase activator, shows renoprotection in hypertensive, diabetic, and metabolic preclinical models of chronic kidney disease
Naunyn Schmiedebergs Arch Pharmacol 2021 Dec;394(12):2363-2379.PMID:34550407DOI:10.1007/s00210-021-02149-4.
Chronic kidney diseaQueryse (CKD) is associated with oxidative stress which can interrupt the nitric oxide (NO)/soluble guanylyl cyclase (sGC) signaling and decrease cyclic guanosine monophosphate (cGMP) production. Low cGMP concentrations can cause kidney damage and progression of CKD. The novel sGC activator Runcaciguat targets the oxidized and heme-free form of sGC, restoring cGMP production under oxidative stress. The purpose of this study is to investigate if Runcaciguat could provide an effective treatment for CKD. Runcaciguat was used for the treatment not only in rat CKD models with different etiologies and comorbidities, namely of hypertensive rats, the renin transgenic (RenTG) rat, and angiotensin-supplemented (ANG-SD) rat, but also in rats with diabetic and metabolic CKD, the Zucker diabetic fatty (ZDF) rat. The treatment duration was 2 to 42 weeks and Runcaciguat was applied orally in doses from 1 to 10 mg/kg/bid. In these different rat CKD models, Runcaciguat significantly reduced proteinuria (urinary protein to creatinine ratio; uPCR). These effects were also significant at doses which did not or only moderately decrease systemic blood pressure. Moreover, Runcaciguat significantly decreased kidney injury biomarkers and attenuated morphological kidney damages. In RenTG rats, Runcaciguat improved survival rates and markers of heart injury. These data demonstrate that the sGC activator Runcaciguat exhibits cardio-renal protection at doses which did not reduce blood pressure and was effective in hypertensive as well as diabetic and metabolic CKD models. These data, therefore, suggest that Runcaciguat, with its specific mode of action, represents an efficient treatment approach for CKD and associated CV diseases.
Soluble GC stimulators and activators: Past, present and future
Br J Pharmacol 2021 Oct 2.PMID:34600441DOI:10.1111/bph.15698.
The discovery of soluble GC (sGC) stimulators and sGC activators provided valuable tools to elucidate NO-sGC signalling and opened novel pharmacological opportunities for cardiovascular indications and beyond. The first-in-class sGC stimulator riociguat was approved for pulmonary hypertension in 2013 and vericiguat very recently for heart failure. sGC stimulators enhance sGC activity independent of NO and also act synergistically with endogenous NO. The sGC activators specifically bind to, and activate, the oxidised haem-free form of sGC. Substantial research efforts improved on the first-generation sGC activators such as cinaciguat, culminating in the discovery of Runcaciguat, currently in clinical Phase II trials for chronic kidney disease and diabetic retinopathy. Here, we highlight the discovery and development of sGC stimulators and sGC activators, their unique modes of action, their preclinical characteristics and the clinical studies. In the future, we expect to see more sGC agonists in new indications, reflecting their unique therapeutic potential.
Discovery of the Soluble Guanylate Cyclase Activator Runcaciguat (BAY 1101042)
J Med Chem 2021 May 13;64(9):5323-5344.PMID:33872507DOI:10.1021/acs.jmedchem.0c02154.
Herein we describe the discovery, mode of action, and preclinical characterization of the soluble guanylate cyclase (sGC) activator Runcaciguat. The sGC enzyme, via the formation of cyclic guanosine monophoshphate, is a key regulator of body and tissue homeostasis. sGC activators with their unique mode of action are activating the oxidized and heme-free and therefore NO-unresponsive form of sGC, which is formed under oxidative stress. The first generation of sGC activators like cinaciguat or ataciguat exhibited limitations and were discontinued. We overcame limitations of first-generation sGC activators and identified a new chemical class via high-throughput screening. The investigation of the structure-activity relationship allowed to improve potency and multiple solubility, permeability, metabolism, and drug-drug interactions parameters. This program resulted in the discovery of the oral sGC activator Runcaciguat (compound 45, BAY 1101042). Runcaciguat is currently investigated in clinical phase 2 studies for the treatment of patients with chronic kidney disease and nonproliferative diabetic retinopathy.
The sGC stimulator BAY-747 and activator Runcaciguat can enhance memory in vivo via differential hippocampal plasticity mechanisms
Sci Rep 2022 Mar 4;12(1):3589.PMID:35246566DOI:10.1038/s41598-022-07391-1.
Soluble guanylate cyclase (sGC) requires a heme-group bound in order to produce cGMP, a second messenger involved in memory formation, while heme-free sGC is inactive. Two compound classes can increase sGC activity: sGC stimulators acting on heme-bound sGC, and sGC activators acting on heme-free sGC. In this rodent study, we investigated the potential of the novel brain-penetrant sGC stimulator BAY-747 and sGC activator Runcaciguat to enhance long-term memory and attenuate short-term memory deficits induced by the NOS-inhibitor L-NAME. Furthermore, hippocampal plasticity mechanisms were investigated. In vivo, oral administration of BAY-747 and Runcaciguat to male Wistar rats enhanced memory acquisition in the object location task (OLT), while only BAY-747 reversed L-NAME induced memory impairments in the OLT. Ex vivo, both BAY-747 and Runcaciguat enhanced hippocampal GluA1-containing AMPA receptor (AMPAR) trafficking in a chemical LTP model for memory acquisition using acute mouse hippocampal slices. In vivo only Runcaciguat acted on the glutamatergic AMPAR system in hippocampal memory acquisition processes, while for BAY-747 the effects on the neurotrophic system were more pronounced as measured in male mice using western blot. Altogether this study shows that sGC stimulators and activators have potential as cognition enhancers, while the underlying plasticity mechanisms may determine disease-specific effectiveness.
Responses in Blood Pressure and Kidney Function to Soluble Guanylyl Cyclase Stimulation or Activation in Normal and Diabetic Rats
Nephron 2022 Oct 20;1-20.PMID:36265461DOI:10.1159/000526934.
Introduction: Agonists of soluble guanylate cyclase (sGC) are being developed as treatment for cardiovascular disease. Most effects of nitric oxide (NO) on glomerular and tubular function are mediated through sGC, but whether sGC agonists mimic these effects is unknown. Methods: Renal clearance and micropuncture studies were performed in Wistar-Froemter rats (WF), with or without streptozotocin diabetes (STZ-WF), and in Goto-Kakizaki rats (GK) with mild type 2 diabetes to test for acute effects of the sGC "stimulator" BAY 41-2272, which synergizes with endogenous NO, and the "activator" Runcaciguat, which generates cGMP independent of NO. Results: Both sGC agonists reduced arterial blood pressure (MAP). For MAP reductions <10%, the drugs increased GFR in WF and STZ-WF but not in GK. Larger MAP reductions outweighed this effect and GFR declined, with better preserved GFR in STZ-WF. Changes in GFR could not be accounted for by changes in RBF, suggesting parallel changes in ultrafiltration pressure and/or ultrafiltration coefficient. The doses chosen for micropuncture in WF and GK reduced MAP by 2-10%, and the net effect on single nephron GFR and ultrafiltration pressure was neutral. The effects of the drugs on tubular reabsorption were dominated by declining MAP, and no natriuretic effect was observed at any dose. Discussion/conclusion: sGC agonists impact kidney function directly and because they reduce MAP. The direct tendency to increase GFR is most apparent for MAP reductions <10%. The direct effect is otherwise subtle and overridden when MAP declines more. Effects of sGC agonists on tubular reabsorption are dominated by the effects on MAP.