| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| 10mg |
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| Other Sizes |
Purity: ≥98%
| Targets |
Soluble guanylate cyclase (sGC) - activator (heme-free form); EC50 = 11.2 ± 1.0 nM in sGC-overexpressing CHO reporter cell line; EC50 = 2.1 ± 0.07 nM in sGC-overexpressing CHO reporter cell line pretreated with ODQ (30 μM, 3 h). [1]
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| ln Vitro |
Runcaciguat (concentrations 0.01 to 100 μM) on highly purified recombinant sGC enzyme exhibited concentration-dependent activation ranging from 2.6-fold (0.01 μM) to 9.3-fold (100 μM) in cGMP production. [1]
Runcaciguat showed additive effects on sGC activity in the presence of NO (DEA/NO, 10 μM) over a wide range of concentrations. [1] In the presence of the sGC inhibitor ODQ (10 μM), which leads to oxidized/heme-free sGC, cGMP production was further increased by Runcaciguat, showing the maximum effect on the heme-free enzyme. [1] Runcaciguat activated the sGC reporter cell line with an EC50 of 11.2 ± 1.0 nM; pretreatment with ODQ (30 μM, 3 h) increased potency (EC50 = 2.1 ± 0.07 nM). [1] Runcaciguat in combination with the NO donor SNAP (10 and 100 nM) showed additive effects. [1] Runcaciguat treatment resulted in maximal luminescence signals of 50-60% compared to cinaciguat in sGC-overexpressing cells. [1] Runcaciguat concentration-dependently inhibited phenylephrine-induced contractions of rabbit saphenous artery rings (IC50 = 199 nM) and rabbit aortic rings (IC50 = 39 nM). [1] Runcaciguat concentration-dependently relaxed porcine coronary artery rings precontracted by the thromboxane agonist U-46619 with an IC50 of 137 nM. [1] In the rat Langendorff heart preparation, Runcaciguat reduced coronary perfusion pressure in a concentration-dependent manner from 10 nM to 10 μM with maximal effect of ~45% at the highest concentration; no effect on heart rate, left ventricular diastolic pressure, or contractility was observed up to the highest concentration tested. [1] |
| ln Vivo |
Runcaciguat (iv bolus 0.03 and 0.1 mg/kg) produced dose-dependent and long-lasting decreases in blood pressure with minor effects on heart rate in anaesthetized rats; effects were more pronounced and longer lasting under ODQ pretreatment. [1]
Runcaciguat (oral 10 mg/kg) caused dose-related and long-lasting decreases in mean arterial blood pressure in conscious normotensive rats with telemetric implants, lowering blood pressure by up to 15%; peak levels within the first hours and maintained over >24 h; 1 and 3 mg/kg had no effect on blood pressure; dose-related reflex tachycardia was noted. [1] Runcaciguat (oral 0.3, 1.0, and 3.0 mg/kg) caused dose-related and long-lasting decreases in mean arterial blood pressure in conscious spontaneously hypertensive rats (SHR), lowering blood pressure by 5-15%; effects peaked within 1-12 h, plateaued for ~17 h, with substantial effect persisting at 24 h after 1.0 and 3.0 mg/kg doses; dose-related transient reflex tachycardia up to 20% was observed. [1] In the L-NAME-treated renin transgenic rat model (TGR(mRenR2)27), Runcaciguat (1, 3, and 10 mg/kg BID, oral) significantly and dose-dependently decreased mortality (58% in placebo, 56% at 1 mg/kg, 39% at 3 mg/kg, 28% at 10 mg/kg; 10 mg/kg statistically significant, 3 mg/kg showed strong trend). [1] Runcaciguat treatment resulted in dose-dependent and significant reduction of proteinuria and significant increase of creatinine clearance at the end of the study, indicating kidney protective effects. [1] Runcaciguat treatment significantly reduced heart hypertrophy (right and left ventricle), indicating cardioprotective effects. [1] |
| Enzyme Assay |
Highly purified recombinant sGC enzyme assay: Runcaciguat was tested in concentrations ranging from 0.01 to 100 μM for its capability to stimulate cGMP production on purified sGC enzyme. Concentration-dependent activation was observed ranging from 2.6-fold (0.01 μM) to 9.3-fold (100 μM). Additive effects with NO (DEA/NO 10 μM) were tested. In the presence of ODQ (10 μM, leading to oxidized/heme-free sGC), cGMP production was further increased. The assay was performed as described previously for characterization of sGC stimulators and sGC activators. [1]
Cell-based cGMP formation assay in sGC-overexpressing CHO cells: A stable CHO reporter cell line overexpressing rat sGC was used. The minimum effective concentration (MEC) was defined as the concentration required to achieve a ≥ threefold stimulation of cGMP formation. EC50 values were determined with a concentration-response curve. For ODQ-pretreatment experiments, cells were incubated with 30 μM ODQ for 3 h before Runcaciguat addition. For combination studies, Runcaciguat was tested with the NO donor SNAP (10 and 100 nM). Luminescence signals were measured and compared to cinaciguat as control. [1] Vasorelaxation assay on isolated vessels: Rabbit saphenous artery rings and rabbit aortic rings were precontracted with phenylephrine, and Runcaciguat was added to determine concentration-dependent inhibition with IC50 values. Porcine coronary artery rings were precontracted with the thromboxane agonist U-46619, and Runcaciguat was added to determine relaxation with IC50 values. [1] Langendorff-perfused heart assay: Rat hearts were perfused in Langendorff preparation; Runcaciguat was tested from 10 nM to 10 μM to assess effects on coronary perfusion pressure, heart rate, left ventricular diastolic pressure, and contractility (+dp/dt). [1] |
| Cell Assay |
sGC-overexpressing CHO reporter cell line assay: Cells were used to assess sGC activation by Runcaciguat; EC50 was determined as 11.2 ± 1.0 nM. Pretreatment with ODQ (30 μM, 3 h) increased potency to EC50 = 2.1 ± 0.07 nM. Combination with the NO donor SNAP (10 and 100 nM) showed additive effects. Maximal luminescence signals reached 50-60% compared to cinaciguat. [1]
Vasorelaxation experiments on isolated vessels: Rabbit saphenous artery, rabbit aortic, and porcine coronary artery rings were used. Tissues were precontracted with phenylephrine or U-46619, then treated with Runcaciguat to determine IC50 values (199 nM for saphenous artery, 39 nM for aortic rings, 137 nM for coronary artery rings). [1] Langendorff-perfused rat heart assay: Rat hearts were mounted in Langendorff apparatus; Runcaciguat was perfused at concentrations from 10 nM to 10 μM; coronary perfusion pressure, heart rate, left ventricular diastolic pressure, and contractility were measured. [1] |
| Animal Protocol |
Anaesthetized rat hemodynamics: Wistar rats were anesthetized; Runcaciguat was administered as intravenous bolus at 0.03 and 0.1 mg/kg; blood pressure and heart rate were monitored. Experiments were performed in the absence and presence of ODQ pretreatment. [1]
Conscious normotensive rat telemetry: Rats with telemetric implants received oral Runcaciguat at 1, 3, and 10 mg/kg; mean arterial blood pressure and heart rate were monitored continuously; effects were assessed over 24 hours. [1] Conscious spontaneously hypertensive rat (SHR) study: SHR received oral Runcaciguat at 0.1, 0.3, 1.0, and 3.0 mg/kg; blood pressure and heart rate were monitored; effects were assessed over 24 hours. [1] Long-term L-NAME-treated renin transgenic rat model: TGR(mRenR2)27 rats were treated with L-NAME to induce endothelial dysfunction; Runcaciguat was administered orally at 1, 3, and 10 mg/kg BID for 7 weeks. Mortality, proteinuria, creatinine clearance, and heart weight were assessed. [1] |
| ADME/Pharmacokinetics |
Pharmacokinetic parameters of Runcaciguat in Wistar rats (iv 0.3 mg/kg): Vss = 1.4 L/kg, CLb = 0.21 L/(h·kg), t1/2 = 7.5 h; po 0.3 mg/kg, bioavailability F = 95%. [1]
Pharmacokinetic parameters of Runcaciguat in Beagle dogs (iv 0.3 mg/kg): Vss = 2.8 L/kg, CLb = 1.4 L/(h·kg), t1/2 = 4.3 h; po 0.3 mg/kg, bioavailability F = 8%. [1] Pharmacokinetic parameters of Runcaciguat in cynomolgus monkeys (iv 0.1 mg/kg): Vss = 1.4 L/kg, CLb = 0.16 L/(h·kg), t1/2 = 10 h; po 0.1 mg/kg, bioavailability F = 81%. [1] Runcaciguat showed no relevant inhibitory effects on major CYP isoforms. [1] |
| Toxicity/Toxicokinetics |
CYP3A4 induction potential: Runcaciguat (compound 45) was evaluated for CYP3A4 induction in primary cultures of human hepatocytes from three donors. The cyclopropyl propionic acid compound 45 ultimately provided the best overall profile with a positive assessment of the predicted safety margin regarding human CYP3A4 induction potential. No relevant inhibitory effects on major CYP isoforms or off-target effects were observed. [1]
No specific toxicity data such as LD50, hepatotoxicity, nephrotoxicity, or plasma protein binding were reported in this study. [1] |
| References | |
| Additional Infomation |
Runcaciguat is a potent and selective sGC activator that activates the oxidized and heme-free form of sGC, which is formed under oxidative stress conditions. This mode of action restores the dysfunctional NO/sGC/cGMP signaling pathway, which is impaired in cardiovascular and cardiorenal diseases. [1]
First-generation sGC activators like cinaciguat (intravenous only, unfavorable PK/PD profile) and ataciguat (weak activity, discontinued in phase 2) had limitations that were overcome with Runcaciguat. [1] X-ray crystal structure of Runcaciguat bound to the Nostoc sp. H-NOX domain (homologous to human sGC, 35% sequence identity) at 2.2 Å resolution (PDB code 7LGK) showed that the carboxylic acid replaces one of the carboxyl-butyl moieties of cinaciguat with the same hydrogen-bond pattern to the YxSxR motif; the second carboxylic acid site is occupied by a chloride ion. The central amide is sandwiched between H105 and W74; the αF helix is shifted ~2 Å from its heme-bound position, opening space for binding the central chlorinated phenyl ring; the cyclopropyl moiety binds into a hydrophobic pocket formed by M1, V5, M144, and W74. [1] Runcaciguat is currently being investigated in clinical phase 2 trials: CONCORD trial (NCT04507061) for chronic kidney disease (CKD) and NEON trial (NCT04722991) for nonproliferative diabetic retinopathy (NPDR). [1] In vitro metabolism data showed a wide and variable distribution of different metabolic pathways including conjugation, oxidative, and hydrolytic reactions. [1] The compound has a favorable profile with low clearance and long half-lives after intravenous administration and high oral bioavailability in rats and monkeys, with moderate clearance and oral bioavailability in dogs. [1] |
| Molecular Formula |
C23H22CL2F3NO3
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|---|---|
| Molecular Weight |
488.326895236969
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| Exact Mass |
487.092
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| Elemental Analysis |
C, 56.57; H, 4.54; Cl, 14.52; F, 11.67; N, 2.87; O, 9.83
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| CAS # |
1402936-61-1
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| Related CAS # |
1402936-61-1;
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| PubChem CID |
134440946
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| Appearance |
White to off-white solid powder
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| LogP |
6.6
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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 |
8
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| Heavy Atom Count |
32
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| Complexity |
665
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| Defined Atom Stereocenter Count |
3
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| SMILES |
ClC1C=CC(=CC=1NC([C@H](C1C=CC(=CC=1)Cl)[C@@H](C)C(F)(F)F)=O)[C@@H](CC(=O)O)C1CC1
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| InChi Key |
NCRMKIWHFXSBGZ-CNBXIYLPSA-N
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| InChi Code |
InChI=1S/C23H22Cl2F3NO3/c1-12(23(26,27)28)21(14-4-7-16(24)8-5-14)22(32)29-19-10-15(6-9-18(19)25)17(11-20(30)31)13-2-3-13/h4-10,12-13,17,21H,2-3,11H2,1H3,(H,29,32)(H,30,31)/t12-,17+,21+/m1/s1
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| Chemical Name |
(3S)-3-{4-chloro-3-[(2S,3R)-2-(4-chlorophenyl)-4,4,4-
trifluoro-3-methylbutanamido]phenyl}-3-
cyclopropylpropanoic acid
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| Synonyms |
BAY-1101042 BAY1101042 Runcaciguat
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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: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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 : ~125 mg/mL (~255.97 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0478 mL | 10.2390 mL | 20.4780 mL | |
| 5 mM | 0.4096 mL | 2.0478 mL | 4.0956 mL | |
| 10 mM | 0.2048 mL | 1.0239 mL | 2.0478 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 |
| NCT04722991 | COMPLETED | Drug: Runcaciguat (BAY1101042)
Other: Placebo |
Diabetic Retinopathy | Bayer | 2021-03-17 | Phase 2 |
| NCT04507061 | COMPLETED | Drug: runcaciguat Other: Placebo |
Chronic Kidney Disease | Bayer | 2020-09-01 | Phase 2 |
| NCT04820621 | TERMINATED | Drug: Runcaciguat (BAY1101042) | Chronic Kidney Disease | Bayer | 2021-04-07 | Phase 1 |
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