H3 receptor ( Ki = 0.16 nM )
Cinaciguat (10 μM) significantly enhances intracellular cGMP production. Cinaciguat has no dose-dependent effects on cell contraction and induces transient changes [2].

Cinaciguat (10 μM) 显着增强细胞内 cGMP 的生成。Cinaciguat 对细胞收缩和诱导瞬时变化没有剂量依赖性影响[2]。

Cinaciguat (10 mg/kg/day，po) 处理糖尿病胆固醇不影响血压水平，但会导致水识别量降低。Cinaciguat 处理可减少糖尿病相关的氧化，预防 DM 相关的 NO-sGC-cGMP- PKG 信号改变改变，并减少 DM 相关的心肌肥大和细胞无菌[1]。 Cinaciguat (1-10-100 nM) 在 WT 和 apo-sGC 小鼠平滑肌条中均引起浓度收缩，但PGF2α对WT或apo-sGC的胃肠平滑肌条的相对活性无影响[3]。

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在链脲佐菌素诱导的1型糖尿病大鼠模型中，长期口服cinaciguat（10 mg/kg/天，持续8周）显著提高了糖尿病动物的血浆cGMP水平，并恢复了心肌cGMP含量。
Cinaciguat治疗减轻了糖尿病相关的心肌硝基氧化应激，表现为硝基酪氨酸免疫反应性降低以及抗氧化/热休克蛋白（HSP70a1、谷胱甘肽还原酶）的mRNA表达正常化。
它通过减少心肌细胞肥大（降低心肌细胞直径和ANF mRNA表达）、减轻间质纤维化（减少Masson三色染色和TGF-β1表达）以及减少DNA断裂（降低TUNEL阳性率）来防止病理性心肌重构。
在功能水平上，cinaciguat改善了左心室（LV）收缩功能的负荷非依赖性指标（增加前负荷可募集搏出功，PRSW）和舒张功能（降低左心室压力衰减时间常数，Tau，以及左心室舒张末压，LVEDP）。射血分数（EF）和搏出功（SW）恢复至非糖尿病对照组的水平。治疗不影响血糖水平，但降低了糖尿病大鼠升高的每日饮水量。在非糖尿病对照大鼠中，cinaciguat未产生显著的血流动力学影响。[1]

Rats are randomized into four groups after DM is confirmed: vehicle-treated control, cinaciguat-treated control, vehicle-treated diabetic, and cinaciguat-treated diabetic groups. Treatment begins immediately upon DM confirmation and lasts for 8 weeks. The animals are given either a 0.5% methylcellulose vehicle or the sGC activator cinaciguat in suspension p.o. (10 mg/kg/day). Daily water consumption is measured and water bottles are filled with the same volume of fresh tap water each morning. To avoid water spilling from the bottles, animal cages are handled carefully and are not moved after the bottles are replaced. Once every two days, the animals' body weight is measured, and the cinaciguat dosage is modified accordingly.

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Type-1 diabetes was induced in 8-week-old male Sprague-Dawley rats by a single intraperitoneal injection of streptozotocin (60 mg/kg). Diabetic rats and non-diabetic controls were randomized to receive either vehicle (0.5% methylcellulose) or cinaciguat (suspended in 0.5% methylcellulose) orally at a dose of 10 mg/kg/day for 8 weeks. The dose was adjusted based on body weight, which was recorded every two days. Drug/vehicle was administered via drinking water; water bottles were refilled daily with a measured amount. Hemodynamic assessment via left ventricular pressure-volume analysis was performed 24-28 hours after the last drug/vehicle administration under anesthesia. [1]

The article mentions that in prior human clinical trials for acute decompensated heart failure, acute intravenous application of cinaciguat led to a significant drop in blood pressure, resulting in a high number of adverse events and premature termination of phase-IIb studies. In the current chronic oral dosing study in rats, cinaciguat treatment did not affect blood glucose levels. It reduced the elevated daily water intake observed in diabetic animals. No other specific toxicities (e.g., organ toxicity, lethality) were reported from this animal study. [1]

[1]. The soluble guanylate cyclase activator cinaciguat prevents cardiac dysfunction in a rat model of type-1 diabetes mellitus. Cardiovasc Diabetol. 2015 Oct 31;14:145.

[2]. The soluble guanylate cyclase stimulator riociguat and the soluble guanylate cyclase activator cinaciguat exert no direct effects on contractility and relaxation of cardiac myocytes from normal rats. Format: AbstractSend to Eur J Pharmaco.

[3]. Influence of cinaciguat on gastrointestinal motility in apo-sGC mice. Neurogastroenterol Motil. 2014 Nov;26(11):1573-85.

Cinaciguat is a benzoic acid that is 4-(aminomethyl)benzoic acid in which the amino group is substituted by 4-carboxybutyl and 2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl groups. It is a soluble guanylate cyclase activator, used for the treatment of acute decompensated heart failure. It has a role as a vasodilator agent, a soluble guanylate cyclase activator and an antihypertensive agent. It is a member of benzoic acids, a tertiary amino compound, an aromatic ether and a dicarboxylic acid.
Cinaciguat is under investigation in clinical trial NCT01067859 (A Phase Iib Study to Investigate the Efficacy and Tolerability of Lower Doses Cinaciguat (25 ΜG/h, 10 ΜG/h) Given Intravenously to Patients With Acute Decompensated Chronic Congestive Heart Failure (ADHF)).

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Cinaciguat (BAY 58-2667) is an sGC activator investigated for its cardioprotective effects in conditions associated with impaired NO-sGC-cGMP signaling, such as diabetic cardiomyopathy. Its mechanism involves activating the oxidized/heme-deficient, NO-insensitive form of sGC that is prevalent under conditions of nitro-oxidative stress, thereby restoring cGMP production and downstream PKG signaling.
This study demonstrates its potential to prevent structural (hypertrophy, fibrosis), molecular (oxidative stress, DNA damage), and functional (systolic and diastolic dysfunction) alterations in the diabetic heart without affecting glycemia.
The authors note that the beneficial effects observed with chronic oral administration in this preclinical model contrast with the hypotensive side effects seen with acute intravenous infusion in heart failure patients, suggesting different risk-benefit profiles based on administration route and clinical context. [1]

C36H39NO5

565.69856

565.282

C, 76.43; H, 6.95; N, 2.48; O, 14.14

329773-35-5

Cinaciguat hydrochloride; 646995-35-9

9808022

White to off-white solid powder

1.2±0.1 g/cm3

731.0±60.0 °C at 760 mmHg

395.9±32.9 °C

0.0±2.5 mmHg at 25°C

1.614

8.14

87.07

2

6

17

42

767

0

OC(C(C=C1)=CC=C1CN(CCCCC(O)=O)CCC(C=CC=C2)=C2OCC(C=C3)=CC=C3CCC4=CC=CC=C4)=O

WPYWMXNXEZFMAK-UHFFFAOYSA-N

InChI=1S/C36H39NO5/c38-35(39)12-6-7-24-37(26-30-19-21-33(22-20-30)36(40)41)25-23-32-10-4-5-11-34(32)42-27-31-17-15-29(16-18-31)14-13-28-8-2-1-3-9-28/h1-5,8-11,15-22H,6-7,12-14,23-27H2,(H,38,39)(H,40,41)

4-[[4-carboxybutyl-[2-[2-[[4-(2-phenylethyl)phenyl]methoxy]phenyl]ethyl]amino]methyl]benzoic acid

BAY 582667; BAY-582667; BAY582667; BAY 58-2667; BAY-58-2667; BAY58-2667; Cinaciguat HCl; Cinaciguat hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~66 mg/mL (~198.6 mM)
Water: ~66 mg/mL
Ethanol: ~66 mg/mL

配方 1 中的溶解度: 2.5 mg/mL (4.42 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 悬浮液；超声助溶。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (4.42 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。