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Purity: ≥98%
Nelociguat (also known as BAY60-4552) is a nitric oxide sensitive soluble guanylate cyclase stimulator (sGC stimulator). In the nitric oxide (NO) signaling pathway, soluble guanylate cyclase (sGC) is a crucial enzyme. Cyclic guanosine monophosphate (cGMP), which boosts vasodilation and inhibits smooth muscle proliferation, leukocyte recruitment, platelet aggregation, and vascular remodelling through a variety of downstream mechanisms, is synthesized by sGC upon binding of NO to its prosthetic haem group.
| Targets |
In the nitric oxide (NO) signaling pathway, soluble guanylate cyclase (sGC) is an essential enzyme[1]. In addition to cytochrome P450 isoenzymes 3A4 (CYP3A4), CYP2C8, and CYP2J2, riciguat is also metabolized to BAY60-4552 via CYP1A1, which is found in the liver and lungs[2].
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| ln Vitro |
In the nitric oxide (NO) signaling pathway, soluble guanylate cyclase (sGC) is an essential enzyme[1]. In addition to cytochrome P450 isoenzymes 3A4 (CYP3A4), CYP2C8, and CYP2J2, riciguat is also metabolized to BAY60-4552 via CYP1A1, which is found in the liver and lungs[2].
BAY 60-4552 increased phosphorylation of vasodilator-stimulated phosphoprotein (P-VASP) in rat aortic smooth muscle cells in a concentration-dependent manner (EC50 = 353 ± 89 nM). Pre-treatment with the sGC heme-site oxidant inhibitor ODQ (10 µM) attenuated this effect, causing a 9.8-fold rightward shift in the concentration-response curve (EC50 = 3,264 ± 737 nM). [1] GSK2181236A increased P-VASP levels in rat aortic smooth muscle cells in a concentration-dependent manner (EC50 = 12.7 ± 4.7 nM). Pre-treatment with ODQ (10 µM) potentiated this effect, causing a 4.7-fold leftward shift (EC50 = 2.7 ± 0.6 nM) and a 32% increase in the maximal response. [1] |
| ln Vivo |
GSK2181236A and BAY 60-4552 offer some protection against end-organ damage brought on by hypertension. A small dose of BAY 60-4552 reduces urine output and increases survival in rats that are prone to spontaneous hypertension and stroke. In addition to lowering microalbuminuria and reducing urine output, a high dose also attenuates the rise in mean arterial pressure. The survival rates of 46 and 69% are increased by BAY 60-4552 at doses of 0.3 and 3 mg/kg/day. Urine output is dose-dependently decreased to 79±11 and 56±10 mL/day after seven weeks of treatment with BAY 60-4552 (0.3 and 3.0 mg/kg/day)[1]. Vardenafil and BAY 60-4552 have synergistic beneficial effects that may be able to save patients who are not responding well to PDE5 inhibitor treatment following radical prostatectomy[3].
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| Animal Protocol |
Rats: Oral gavage of rats is performed two hours before ischemia with vehicle (0.5% HPMC, 5% DMSO, and 0.1% Tween 80; 10 mL/kg; n=14), GSK2181236A (0.1 or 1.0 mg/kg; n=11–14), or BAY 60-4552 (0.3 or 3.0 mg/kg; n=10–12). Both when ischemia first occurs and 24 hours after reperfusion, blood is drawn. For analysis, plasma is obtained[1].
For the myocardial ischemia/reperfusion (I/R) injury study in Sprague Dawley rats, compounds were administered via oral gavage 2 hours prior to coronary artery occlusion. BAY 60-4552 was tested at 0.3 and 3.0 mg/kg, and GSK2181236A at 0.1 and 1.0 mg/kg, using a vehicle of 0.5% hydroxypropyl methylcellulose, 5% dimethylsulfoxide, and 0.1% Tween 80 at a volume of 10 mL/kg. [1] For the chronic study in spontaneously hypertensive stroke-prone rats (SHR-SP) on a high salt/fat diet (HSFD), compounds were administered chronically mixed in the diet for 7 weeks, starting 1 week after initiation of the HSFD. Doses were: BAY 60-4552 at 0.3 and 3.0 mg/kg/day, and GSK2181236A at 0.1 and 1.0 mg/kg/day. [1] |
| ADME/Pharmacokinetics |
Riociguat and its pharmacologically active metabolite M1 (BAY 60-4552) exhibit near-dose-proportional pharmacokinetic characteristics after single and multiple administrations (1 mg and 2 mg three times daily). After a single dose, the mean terminal elimination half-life (t1/2) of riociguat ranges from 2.12 to 5.69 hours, depending on dose and smoking status. At steady state, the t1/2 of riociguat ranges from 2.80 to 8.31 hours. Compared to non-smokers, smokers have significantly lower (≥ 60%) riociguat exposures, with a smaller effect on metabolite M1 exposure. Drug accumulation is extremely low in smokers, while it is approximately twice that in non-smokers (based on AUC accumulation ratio). Riociguat is metabolized by cytochrome P450. P450 isoenzymes CYP1A1, CYP3A4, CYP2C8 and CYP2J2.
Riociguat (parent and metabolites) is mainly excreted via the kidneys (33-45%) and bile/feces (48-59%). [2] |
| Toxicity/Toxicokinetics |
The most frequently reported adverse events related to treatment were gastroesophageal reflux disease (8 out of 12 subjects in the riociguat 2 mg group). All adverse events were mild or moderate and resolved by the end of the study. Riociguat did not cause any clinically relevant changes in laboratory parameters, electrocardiograms (including QTc intervals), or vital signs. [2]
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| References |
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| Additional Infomation |
Nelociguat belongs to the pyrazolopyridine class of compounds, with the chemical formula 1H-pyrazolo[3,4-b]pyridine, substituted at positions 1 and 3 by 2-fluorobenzyl and 4,6-diamino-5-[(methoxycarbonyl)amino]pyrimidine-2-yl, respectively. It is the active metabolite of riociguat and a soluble guanylate cyclase activator developed by Bayer for the treatment of erectile dysfunction and heart failure. It has multiple functions, including as a soluble guanylate cyclase activator, an antihypertensive drug, a drug metabolite, and a vasodilator. It is a pyrazolopyridine compound belonging to the monofluorobenzene, carbamate, and aminopyrimidine classes. This study investigated the pharmacokinetics, safety, and tolerability of the soluble guanylate cyclase (sGC) stimulator riociguat in healthy young Chinese non-smokers and smokers. This is the first study to provide pharmacokinetic data for riocigua in the Chinese population. The results showed that smoking status significantly affected riocigua exposure, possibly because smoking induces the expression of the metabolic enzyme CYP1A1. [2]
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| Molecular Formula |
C19H17FN8O2
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|---|---|
| Molecular Weight |
408.38908
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| Exact Mass |
408.145
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| Elemental Analysis |
C, 55.88; H, 4.20; F, 4.65; N, 27.44; O, 7.84
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| CAS # |
625115-52-8
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| PubChem CID |
11690019
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.6±0.1 g/cm3
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| Boiling Point |
533.3±50.0 °C at 760 mmHg
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| Flash Point |
276.3±30.1 °C
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| Vapour Pressure |
0.0±1.4 mmHg at 25°C
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| Index of Refraction |
1.748
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| LogP |
-0.1
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
30
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| Complexity |
589
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(OC)NC1=C(N)N=C(C2=NN(CC3=CC=CC=C3F)C4=NC=CC=C42)N=C1N
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| InChi Key |
FTQHGWIXJSSWOY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H17FN8O2/c1-30-19(29)24-14-15(21)25-17(26-16(14)22)13-11-6-4-8-23-18(11)28(27-13)9-10-5-2-3-7-12(10)20/h2-8H,9H2,1H3,(H,24,29)(H4,21,22,25,26)
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| Chemical Name |
methyl N-[4,6-diamino-2-[1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl]carbamate
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| Synonyms |
Nelociguat; BAY604552; BAY-604552; BAY 604552; BAY60-4552; BAY 60-4552; BAY-60-4552
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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: < 1 mg/mL
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.09 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (5.09 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (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 20.8 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4486 mL | 12.2432 mL | 24.4864 mL | |
| 5 mM | 0.4897 mL | 2.4486 mL | 4.8973 mL | |
| 10 mM | 0.2449 mL | 1.2243 mL | 2.4486 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.
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