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Purity: ≥98%
Cinaciguat HCl, the hydrochloride salt of 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 |
Guanylate cyclase ( EC50 = 15 nM )
In the intermittent setting, cinaciguat hydrochloride (BAY 58-2667) is a potent GC activator (EC50 15 nM), but the maximum effect is around 1% of NO. The concentration response curve of cinaciguat hydrochloride in the presence of sildenafil in the absence of ODQ, with an EC50 of 18 nM, and in the presence of ODQ, there was no significant difference in the efficacy of cinaciguat hydrochloride, with an EC50 of 13 nM. The efficacy of cinaguat hydrochloride in the distal end (EC50 15 nM) was very similar to the estimate achieved for sealed recombinant GC. Cinaciguat hydrochloride at a maximum effective concentration of 1 μM stimulated control GC activity to approximately 25% of the activity observed with NO, and compared with stimulation with NO, this activity remained at lower levels as the proportion of ODQ-cut GC increased. Change[1]. |
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| ln Vitro |
In the intermittent setting, cinaciguat hydrochloride (BAY 58-2667) is a potent GC activator (EC50 15 nM), but the maximum effect is around 1% of NO. The concentration response curve of cinaciguat hydrochloride in the presence of sildenafil in the absence of ODQ, with an EC50 of 18 nM, and in the presence of ODQ, there was no significant difference in the efficacy of cinaciguat hydrochloride, with an EC50 of 13 nM. The efficacy of cinaguat hydrochloride in the distal end (EC50 15 nM) was very similar to the estimate achieved for sealed recombinant GC. Cinaciguat hydrochloride at a maximum effective concentration of 1 μM stimulated control GC activity to approximately 25% of the activity observed with NO, and compared with stimulation with NO, this activity remained at lower levels as the proportion of ODQ-cut GC increased. Change[1].
On purified bovine lung sGC, BAY 58-2667 stimulated control (sham-treated) enzyme activity to about 25% of that observed with 10 µM DEA/NO. This activity was attributed to the presence of haem-free protein in the preparation. When the haem was completely removed (using Tween-20 pretreatment), BAY 58-2667 activated the enzyme almost as effectively as NO did under control conditions. In contrast, pretreatment with the haem-oxidizing agent ODQ did not enhance the stimulatory effect of BAY 58-2667 on the purified enzyme. In intact rat platelets, BAY 58-2667 was a potent activator of sGC (EC50 ~15 nM). However, its maximal activity was only about 1% of the peak activity achievable with a saturating NO concentration (50 nM). Pre-treatment of platelets with ODQ (10 µM) to oxidize the haem increased the maximum efficacy of BAY 58-2667 by approximately 22-fold, indicating a significant increase in the proportion of haem-free sGC under these conditions. Even the low level of cGMP generated by BAY 58-2667 alone (1% of maximum NO effect) was sufficient to evoke significant phosphorylation of vasodilator-stimulated phosphoprotein (VASP), a downstream target of cGMP-dependent protein kinase, in platelets. [1] |
| ln Vivo |
Administration of cinaguat hydrochloride reduced blood pressure and increased heart rate in apo-sGC and WT mice. The antihypertensive effect of cinagua hydrochloride was more significant and longer-lasting in apo-sGC mice than in WT mice. In addition, cinagua hydrochloride reduced blood pressure in apo-sGC mice at a concentration that did not affect blood glucose in WT mice. In addition, the IC50 value of cinagua hydrochloride-induced ex vivo contraction of precontracted aortas was threefold lower in apo-sGC mice than in WT mice (IC50=0.2 nM and 0.7 nM, respectively). In summary, our results indicate that sGC activators like Cinaciguat hydrochloride activate apo-sGC as well as sGC stimulators like BAY 41-2272. Additionally, the observation that cinaciguat hydrochloride modulates vasodilation and blood pressure in WT mice suggests that even in healthy mice, a subset of the available sGC pool clears heme and is responsive to sGC activators [2].
In apo‑sGC mice, intravenous administration of cinaciguat (300 µg·kg⁻¹) decreased mean arterial pressure (MAP) and increased heart rate (HR). The blood‑pressure‑lowering effect of cinaciguat was significantly greater and longer‑lasting in apo‑sGC mice than in wild‑type (WT) mice. [2] Cinaciguat also decreased blood pressure in wild‑type mice, suggesting that even in healthy mice a subset of the sGC pool is haem‑free and responsive to sGC activators. [2] In a model of TNF‑induced systemic shock, cinaciguat was shown to improve organ function and survival when administered in the appropriate treatment window. [2] |
| Enzyme Assay |
Platelet suspension aliquots are taken out prior to and periodically following the addition of spermine NONOate or Cinaciguat. They are then promptly transferred into an inactivation buffer (50 mM Tris, 4 mM EDTA, pH 7.4) and kept at 100°C for a minimum of 10 minutes. When using, add 10 μM ODQ to the platelets 15 minutes prior to adding spermine NONOate. After being stimulated with either DEA/NO (10 μM) or Cinaciguat (1 μM), and with enzyme inactivation carried out as with platelets, purified GC activity is measured at a final concentration of 50 ng/mL in assay buffer (50 mM Tris, 100 μM EDTA, 1 mM NaGTP, 1.3 mM MgCl2, 50 μg/mL BSA, pH 7.4). Through the use of radioimmunoassay, the levels of cGMP are determined and expressed in relation to protein content. Each experiment consists of three independent runs, with the results shown as means±s.e.mean[1].
Guanylate cyclase (GC) activity was measured using purified enzyme from bovine lung. The enzyme (5 µg/ml) was diluted in buffer containing Tris, dithiothreitol, and BSA. For some experiments, the enzyme was pre-treated for 15 min at 37°C with 10 µM ODQ (haem-oxidized form) or 0.5% Tween-20 (haem-free form). Control enzyme received solvent (0.5% DMSO). After pretreatment and optional mixing with control enzyme, samples were centrifuged through size-exclusion filters to remove small molecules. GC activity was measured at a final enzyme concentration of 50 ng/ml in assay buffer containing Tris, EDTA, GTP, and MgCl₂. Reactions were stimulated with either the NO donor DEA/NO (10 µM) or BAY 58-2667 (1 µM) for 2 minutes at 37°C, then terminated by heat inactivation. Generated cGMP levels were quantified by radioimmunoassay. [1] To study haem loss kinetics, purified GC was incubated at 37°C with substrate (GTP) and 1 µM BAY 58-2667, with or without 10 µM ODQ. cGMP was measured at various time points. [1] |
| Cell Assay |
This study did not employ traditional cell culture-based assays. The primary cellular model was freshly isolated rat platelets. Functional sGC activity and downstream signaling were assessed in these intact cells. [1]
Platelet cGMP Assay: Rat platelets were suspended and incubated. Aliquots were withdrawn at various times after addition of BAY 58-2667 or an NO donor and immediately transferred into hot inactivation buffer. cGMP levels were measured by radioimmunoassay and expressed relative to protein content. To eliminate complications from cGMP degradation, experiments were often performed in the presence of the phosphodiesterase-5 inhibitor sildenafil (100 µM). cGMP accumulation curves were analyzed to extract kinetic parameters of sGC activity (synthesis rate) and desensitization. [1] VASP Phosphorylation Assay: Platelets were incubated for 2 minutes with test compounds (e.g., BAY 58-2667, DEA/NO) with or without sildenafil or ODQ. Reactions were stopped by boiling in Laemmli buffer. Proteins were separated by SDS-PAGE, transferred to a membrane, and probed with a monoclonal antibody specific for VASP phosphorylated at Ser²³⁹. Bands were detected by enhanced chemiluminescence and quantified by densitometry. [1] |
| Animal Protocol |
Mice: The tail tip of 12 week old male and female mice is removed with a sharp razor blade, leaving 0.5 cm of tail tip exposed. The tail tip is then placed into freshly prepared, 37°C pre-warmed PBS. By using a chronometer and visual scoring, an observer who is blind to the genotype records the latency until the tail stops bleeding. With an awake mouse tail-cuff method, Hatteras MC4000 Blood Pressure Analysis System measures systolic blood pressure (SBP) and heart rate (HR) non-invasively. The BP measuring apparatus takes seven days to acclimate mice to. Mice are measured for five days, with 15 consecutive cycles per day, in order to establish basal BP. The following are administered intraperitoneally: L-NAME (100 mg/kg), SNP (1.5 mg/kg), DETA-NO (60 mg/kg), BAY 41-2772 (4 mg/kg), Cinaciguat (30 μg/kg), and the vehicle controls (PBS or, in the case of the BAY-compounds, 20% Cremophor+20% diethylene-glycol-monoethylether in PBS). SBP measurements are taken 5 to 15 minutes after SNP injection; L-NAME and DETA-NO recordings are taken 1 to 25 minutes after injection; and BAY-compounds recordings are taken 10 to 25 minutes after injection.
For telemetric blood‑pressure measurements, mice were implanted with a PA‑C10 transmitter in the carotid artery. After 7 days recovery, cinaciguat (300 µg·kg⁻¹) or vehicle (20% Cremophor + 20% diethylene‑glycol‑monoethyl‑ether in PBS) was administered intravenously. Blood pressure and heart rate were recorded continuously before and after injection. [2] For aortic‑ring relaxation studies, thoracic aortas from mice were cut into 2‑mm rings and mounted in an organ bath containing Krebs‑Ringer bicarbonate solution at 37 °C. After equilibration and pre‑contraction with phenylephrine, cumulative concentrations of cinaciguat (1 nmol·L⁻¹ to 1 µmol·L⁻¹) were added, and isometric tension was recorded. [2] |
| References | |
| Additional Infomation |
BAY 58-2667 (Sinasig) is the prototype compound of a novel soluble guanylate cyclase (sGC) activator. Its mechanism of action differs from NO; it does not require a heme group for activation. Instead, it binds with high affinity to the heme-free form of sGC, acting as a heme mimic to restore its catalytic activity. Studies have shown that under normal physiological conditions, only a small fraction (approximately 2%) of sGC in rat platelets exists in a heme-free state and can be activated by BAY 58-2667. ODQ significantly enhances the efficacy of this compound (22-fold) in heme oxidation. Its mechanism of action is not to directly act on the oxidized heme itself, but rather to promote heme loss, thereby increasing the content of heme-free sGC. The rapid desensitization (85% loss) of NO-induced sGC activity in platelets is independent of changes in the free enzyme ratio, indicating that heme loss is not the mechanism of this desensitization. This study highlights the utility of BAY 58-2667 as a pharmacological tool for detecting intracellular sGC heme binding status. Its enhanced potency under oxidative stress (which promotes heme loss) suggests its therapeutic potential in diseases with sGC heme deficiency. [1]
|
| Molecular Formula |
C36H40CLNO5
|
|---|---|
| Molecular Weight |
602.1595
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| Exact Mass |
601.259
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| Elemental Analysis |
C, 71.81; H, 6.70; Cl, 5.89; N, 2.33; O, 13.28
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| CAS # |
646995-35-9
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| Related CAS # |
Cinaciguat; 329773-35-5
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| PubChem CID |
10031513
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
17
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| Heavy Atom Count |
43
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| Complexity |
767
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| Defined Atom Stereocenter Count |
0
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| SMILES |
Cl[H].O(C([H])([H])C1C([H])=C([H])C(=C([H])C=1[H])C([H])([H])C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H])C1=C([H])C([H])=C([H])C([H])=C1C([H])([H])C([H])([H])N(C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1C(=O)O[H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(=O)O[H]
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| InChi Key |
LLHMBJOVHATVSP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C36H39NO5.ClH/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);1H
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| Chemical Name |
4-[[4-carboxybutyl-[2-[2-[[4-(2-phenylethyl)phenyl]methoxy]phenyl]ethyl]amino]methyl]benzoic acid;hydrochloride
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| Synonyms |
BAY 582667 HCl; BAY-582667 HCl; BAY582667 HCl; 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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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: ~110 mg/mL (~182.7 mM)
H2O: < 0.1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.75 mg/mL (4.57 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 27.5 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 | 1.6607 mL | 8.3034 mL | 16.6069 mL | |
| 5 mM | 0.3321 mL | 1.6607 mL | 3.3214 mL | |
| 10 mM | 0.1661 mL | 0.8303 mL | 1.6607 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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