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| 1mg |
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| 10mg |
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| Targets |
Rolofylline targets the adenosine A1 receptor (A1AR). It is a potent and selective antagonist of this receptor, with a Ki of 0.19 nM and 890-fold selectivity for A1AR over A2A receptors. By blocking A1AR, it prevents adenosine-induced vasoconstriction of renal afferent arterioles and tubuloglomerular feedback, promoting diuresis and natriuresis while protecting renal function.
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| ln Vitro |
Rolofylline is a potent A1AR antagonist with a Ki of 0.19 nM and 890-fold selectivity for A1AR over A2A receptors. In preclinical studies, it increases urine output up to 69% over placebo while preserving or improving GFR (+32% in CHF models). This demonstrates its potent and selective in vitro and in vivo activity.
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| ln Vivo |
Rolofylline has been evaluated in the largest A1AR antagonist trial (PROTECT, n=2,033) with comprehensive safety and PK data. In preclinical studies, it increases urine output and enhances natriuresis while protecting against diuretic-induced renal deterioration. However, its clinical development for ADHF did not lead to regulatory approval.
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| Enzyme Assay |
The in vitro activity of Rolofylline is assessed using radioligand binding assays. Membrane preparations from cells expressing human A1AR or A2A receptors are incubated with a labeled adenosine receptor ligand in the presence of various concentrations of Rolofylline. The Ki values and selectivity ratios are calculated from displacement curves.
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| Cell Assay |
Cell-based assays are used to evaluate Rolofylline's antagonist activity. Cells expressing A1AR are treated with an A1AR agonist (such as CPA or CHA) in the presence or absence of Rolofylline. The compound's ability to block agonist-induced inhibition of cAMP accumulation (A1AR is coupled to Gi and inhibits adenylyl cyclase) is measured. IC50 or Kb values are calculated from dose-response curves.
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| Animal Protocol |
Rolofylline has been evaluated in animal models of heart failure and renal impairment. In these studies, the compound is typically administered orally or intravenously, and its effects on urine output, GFR, renal blood flow, and hemodynamic parameters are assessed. It has also been studied in the PROTECT clinical trial in patients with ADHF.
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| ADME/Pharmacokinetics |
Rolofylline has a molecular weight of 356.5 g/mol and a molecular formula of C20H28N4O2. Its IUPAC name is 8-(hexahydro-2,5-methanopentalen-3a(1H)-yl)-3,9-dihydro-1,3-dipropyl-1H-purine-2,6-dione. It is soluble in DMSO but not in water. Powder should be stored at -20°C for long-term stability.
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| Toxicity/Toxicokinetics |
Rolofylline has been extensively studied in clinical trials, and its safety profile is well characterized. In the PROTECT trial (n=2,033), comprehensive safety data was collected. As an A1AR antagonist, it can affect renal function and cardiovascular parameters. Common side effects may include headache, dizziness, and gastrointestinal effects. Its development for ADHF did not lead to regulatory approval.
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| Additional Infomation |
Rolofylline is an oxypurine drug. Rolofylline is currently being clinically developed by the pharmaceutical company NovaCardia for the treatment of congestive heart failure. Drug Indications: Heart failure Mechanism of Action: Rolofylline is an adenosine A1 receptor antagonist. Patients with heart failure have elevated plasma adenosine levels, and adenosine A1 receptors in the kidneys mediate vasoconstriction in the bulbar arterioles, reabsorption of sodium and water in the proximal tubules, and tubuloglomerular feedback in the juxtaglomerular apparatus. Therefore, inhibiting these receptors is expected to increase renal blood flow and enhance diuresis. The effects of Rolofylline on renal function are consistent with those observed in experimental and human models of heart failure with another adenosine A1 receptor antagonist.
Rolofylline (CAS#: 136199-02-5) is a potent and selective adenosine A1 receptor antagonist, also known as KW-3902 and MK-7418. It has a Ki of 0.19 nM and 890-fold selectivity for A1AR over A2A receptors. Rolofylline increases urine output while preserving GFR and was evaluated in the largest A1AR antagonist trial (PROTECT, n=2,033). It is a valuable research tool for studying adenosine receptor pharmacology and cardiorenal physiology. |
| Molecular Formula |
C20H28N4O2
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|---|---|
| Molecular Weight |
356.47
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| Exact Mass |
356.221
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| CAS # |
136199-02-5
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| PubChem CID |
64627
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.262g/cm3
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| Boiling Point |
578ºC at 760mmHg
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| Flash Point |
303.4ºC
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| Vapour Pressure |
2.33E-13mmHg at 25°C
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| Index of Refraction |
1.605
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| LogP |
2.784
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
26
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| Complexity |
609
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCCN1C2=C(C(=O)N(CCC)C1=O)N=C(C34CC5CC(CC3C5)C4)N2
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| InChi Key |
PJBFVWGQFLYWCB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H28N4O2/c1-3-5-23-16-15(17(25)24(6-4-2)19(23)26)21-18(22-16)20-10-12-7-13(11-20)9-14(20)8-12/h12-14H,3-11H2,1-2H3,(H,21,22)
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| Chemical Name |
1,3-dipropyl-8-(3-tricyclo[3.3.1.03,7]nonanyl)-7H-purine-2,6-dione
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| Synonyms |
KW3902; KW 3902; KW-3902
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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 : ~20 mg/mL (~56.11 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 | 2.8053 mL | 14.0264 mL | 28.0529 mL | |
| 5 mM | 0.5611 mL | 2.8053 mL | 5.6106 mL | |
| 10 mM | 0.2805 mL | 1.4026 mL | 2.8053 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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