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Purity: ≥98%
Cinaciguat (formerly also known as BAY582667 or BAY58-2667) is a novel and potent activator of soluble guanylate cyclase (sGC) used for acute decompensated heart failure. In a rat model of type-1 diabetes mellitus, ciprofloxacin avoids cardiac dysfunction. Cinaciguat has no direct effects on the relaxation and contractility of cardiac myocytes from rats that are normal. By reducing the migration and proliferation of vascular smooth muscle cells following arterial injury, cipracapat inhibits the formation of neointima.
| Targets |
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]. |
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| ln Vitro |
Cinaciguat (10 μM) significantly enhances intracellular cGMP production. Cinaciguat has no dose-dependent effects on cell contraction and induces transient changes [2].
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| ln Vivo |
Cinaciguat (10 mg/kg/day, po) treatment of diabetic cholesterol did not affect blood pressure levels but resulted in reduced water recognition. Cinaciguat treatment reduces diabetes-associated oxidation, prevents DM-associated alterations in NO-sGC-cGMP-PKG signaling, and reduces DM-associated cardiac hypertrophy and cellular sterility [1]. Cinaciguat (1-10-100 nM) caused concentration contraction in smooth muscle strips of both WT and apo-sGC mice, but PGF2α had no effect on the relative activity of gastrointestinal smooth muscle strips of WT or apo-sGC [3].
In a rat model of streptozotocin-induced type-1 diabetes mellitus (DM), chronic oral treatment with cinaciguat (10 mg/kg/day for 8 weeks) significantly increased plasma cGMP levels and restored myocardial cGMP content in diabetic animals. Cinaciguat treatment alleviated DM-related myocardial nitro-oxidative stress, as evidenced by reduced nitrotyrosine immunoreactivity and normalized mRNA expression of antioxidant/heatshock proteins (HSP70a1, glutathione-reductase). It prevented pathological myocardial remodeling by reducing cardiomyocyte hypertrophy (decreased cardiomyocyte diameter and ANF mRNA expression), attenuating interstitial fibrosis (reduced Masson's trichrome staining and TGF-β1 expression), and decreasing DNA fragmentation (reduced TUNEL positivity). At the functional level, cinaciguat improved load-independent indices of left ventricular (LV) contractility (increased preload recruitable stroke work, PRSW) and diastolic function (decreased time constant of LV pressure decay, Tau, and LV end-diastolic pressure, LVEDP). Ejection fraction (EF) and stroke work (SW) were restored to levels of non-diabetic controls. Treatment did not affect blood glucose levels but reduced the elevated daily water intake in diabetic rats. In non-diabetic control rats, cinaciguat had no significant hemodynamic effects. [1] |
| Animal Protocol |
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.
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] |
| Toxicity/Toxicokinetics |
The article mentions that in previous human clinical trials for acute decompensated heart failure, acute intravenous administration of cinasciguat caused a significant drop in blood pressure, resulting in numerous adverse events and premature termination of the Phase IIb study. In this current rat study of chronic oral administration, cinasciguat treatment did not affect blood glucose levels. It reduced the increase in daily water intake observed in diabetic animals. No other specific toxicities (e.g., organ toxicity, lethality) were reported in this animal study. [1]
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| References |
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| Additional Infomation |
Cinacigua is a benzoic acid compound with the chemical name 4-(aminomethyl)benzoic acid, in which the amino group is replaced by 4-carboxybutyl and 2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl. It is a soluble guanylate cyclase activator used to treat acute decompensated heart failure. It has vasodilatory, soluble guanylate cyclase activating, and antihypertensive pharmacological effects. It belongs to the benzoic acid class, tertiary amine class, aromatic ether class, and dicarboxylic acid class. Cinacigua is currently being investigated in the clinical trial NCT01067859 (a phase IIb study investigating the efficacy and tolerability of intravenously administered low-dose cinascigua (25 μg/h, 10 μg/h) in patients with acute decompensated chronic congestive heart failure (ADHF).
Sinacigua (BAY 58-2667) is a soluble guanylate cyclase (sGC) activator currently under investigation for its cardioprotective effects in diseases associated with impaired NO-sGC-cGMP signaling pathways, such as diabetic cardiomyopathy. Its mechanism of action involves activating an oxidative/heme-deficient, NO-insensitive form of sGC that is prevalent under nitrogenic stress, thereby restoring cGMP production and downstream PKG signaling. This study suggests that the drug has the potential to prevent structural (hypertrophy, fibrosis), molecular (oxidative stress, DNA damage), and functional (systolic and diastolic dysfunction) changes in the diabetic heart without affecting blood glucose levels. The authors noted that the beneficial effects of long-term oral administration observed in this preclinical model contrasted with the hypotensive side effects seen in acute intravenous infusion in patients with heart failure, suggesting that different routes of administration and clinical contexts can lead to different risk-benefit ratios. [1] |
| Molecular Formula |
C36H39NO5
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|---|---|
| Molecular Weight |
565.69856
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| Exact Mass |
565.282
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| Elemental Analysis |
C, 76.43; H, 6.95; N, 2.48; O, 14.14
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| CAS # |
329773-35-5
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| Related CAS # |
Cinaciguat hydrochloride; 646995-35-9
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| PubChem CID |
9808022
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
731.0±60.0 °C at 760 mmHg
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| Flash Point |
395.9±32.9 °C
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| Vapour Pressure |
0.0±2.5 mmHg at 25°C
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| Index of Refraction |
1.614
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| LogP |
8.14
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
17
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| Heavy Atom Count |
42
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| Complexity |
767
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| Defined Atom Stereocenter Count |
0
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| SMILES |
OC(C(C=C1)=CC=C1CN(CCCCC(O)=O)CCC(C=CC=C2)=C2OCC(C=C3)=CC=C3CCC4=CC=CC=C4)=O
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| InChi Key |
WPYWMXNXEZFMAK-UHFFFAOYSA-N
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| InChi Code |
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)
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| Chemical Name |
4-[[4-carboxybutyl-[2-[2-[[4-(2-phenylethyl)phenyl]methoxy]phenyl]ethyl]amino]methyl]benzoic acid
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| Synonyms |
BAY 582667; BAY-582667; BAY582667; BAY 58-2667; BAY-58-2667; BAY58-2667; Cinaciguat HCl; Cinaciguat hydrochloride
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~66 mg/mL (~198.6 mM)
Water: ~66 mg/mL Ethanol: ~66 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (4.42 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.42 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7677 mL | 8.8386 mL | 17.6772 mL | |
| 5 mM | 0.3535 mL | 1.7677 mL | 3.5354 mL | |
| 10 mM | 0.1768 mL | 0.8839 mL | 1.7677 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00559650 | Terminated | Drug: Placebo Drug: Cinaciguat (BAY58-2667) |
Congestive Heart Failure | Bayer | December 2007 | Phase 2 |
| NCT01067859 | Terminated | Drug: Placebo Drug: Cinaciguat (BAY58-2667) |
Acute Heart Failure | Bayer | March 2010 | Phase 2 |
| NCT01064037 | Terminated | Drug: Placebo Drug: Cinaciguat (BAY58-2667) |
Heart Decompensation Heart Failure |
Bayer | April 2010 | Phase 2 |
| NCT01065077 | Terminated | Drug: Placebo Drug: Cinaciguat (BAY58-2667) |
Acute Heart Failure | Bayer | March 2010 | Phase 2 |
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