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| Targets |
IC50: 0.6 µM (Lysophosphatidic acid acyltransferase)[1] STAT4[1]
(R)-Lisofylline targets lysophosphatidic acid acyltransferase (LPAAT), an enzyme involved in the biosynthesis of lysophosphatidic acid and other bioactive lipids, with an IC₅₀ of 0.6 μM. The compound also modulates inflammatory pathways, including suppression of IFN-γ production. As the (R)-enantiomer of the Pentoxifylline metabolite, (R)-Lisofylline exhibits anti-inflammatory activities that are distinct from the parent compound. The compound's effects on insulin secretion and glucose metabolism suggest it may target pathways involved in pancreatic β-cell function and immune regulation. The compound's multi-target profile contributes to its diverse biological activities. |
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| ln Vitro |
(R)-Lisofylline has no effect on IL-12 release from APCs ex vivo or in vitro, but it inhibits IL-12-driven Th1 differentiation and T cell proliferation in vitro[3].
In vitro studies have demonstrated that (R)-Lisofylline is an inhibitor of LPAAT with an IC₅₀ of 0.6 μM. The compound lessens the impairment of insulin secretion induced by IL-1β in cultured rat islet cells. (R)-Lisofylline suppresses IFN-γ production, indicating its anti-inflammatory activity. In cell-based assays, the compound shows protective effects on pancreatic β-cells against cytokine-induced damage. The compound's activity is concentration-dependent and enantiomer-specific, with the (R)-enantiomer showing distinct biological properties compared to the (S)-enantiomer or the racemic mixture. (R)-Lisofylline has been used to study the mechanisms of β-cell dysfunction and inflammation in diabetes. |
| ln Vivo |
(R)-Lisofylline enhances insulin response and lowers glucose levels in Streptozotocin-treated rats after the oral glucose tolerance test. It also lessens the impairment of insulin secretion induced by IL-1β in cultured rat islet cells, suppresses IFN-γ production, the onset of diabetes, and macrophage infiltration into islets from NOD mice[1]. (R)-Lisofylline inhibits STAT4 phosphorylation, which stops IL-12 signaling, preventing β cell dysfunction in NOD mice. In mice, (R)-Lisofylline reduces the symptoms of experimental allergic encephalomyelitis[1]. (R)-Lisofylline also lessens sepsis-induced lung damage in minipigs and increases survival in mice given a fatal dosage of LPS injections. While pretreatment with (R)-Lisofylline lowers lung leak in rats given IL-1 intratracheally, it does not lessen the concentration of neutrophils in the lungs[1]. (R)-Lisofylline also inhibits the release of TNF-α when endotoxins from Salmonella or Escherichia coli are triggered in vivo in mice and ex vivo in human blood[1].
In vivo studies have demonstrated that (R)-Lisofylline enhances insulin response and lowers glucose levels in streptozotocin-treated rats after oral glucose tolerance testing. In NOD (non-obese diabetic) mice, the compound suppresses IFN-γ production, delays the onset of diabetes, and reduces macrophage infiltration into islets. These findings suggest that (R)-Lisofylline has protective effects against the development of autoimmune diabetes. The compound's anti-inflammatory and immunomodulatory activities contribute to its in vivo efficacy. (R)-Lisofylline has been investigated in animal models of diabetes and inflammation. |
| Enzyme Assay |
Cell-free biochemical assays for (R)-Lisofylline typically measure inhibition of LPAAT activity. A standard protocol involves incubating recombinant LPAAT or lysates from cells expressing LPAAT with varying concentrations of (R)-Lisofylline (0.01-100 μM), a lysophosphatidic acid substrate, and acyl-CoA in appropriate buffer. Product formation is detected by radiometric methods using [¹⁴C]-labeled substrates or by mass spectrometry. IC₅₀ values are determined from dose-response curves using nonlinear regression analysis. Assays are performed in triplicate with appropriate positive and negative controls. The compound's enantiomeric purity is verified by chiral HPLC.
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| Cell Assay |
Cellular assays for (R)-Lisofylline typically use pancreatic β-cell lines or primary islet cells to assess effects on insulin secretion and cell survival. A standard protocol involves culturing rat islet cells or β-cell lines (e.g., INS-1, MIN6) in 96-well plates, treating with (R)-Lisofylline at concentrations ranging from 1-100 μM for 1-48 hours, and stimulating with glucose or cytokines (e.g., IL-1β). Insulin secretion is measured by ELISA or RIA. Cell viability is assessed by MTT or apoptosis assays. Cytokine-induced damage is assessed by measuring nitric oxide production or caspase activity. IFN-γ production is measured in immune cell cultures by ELISA.
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| Animal Protocol |
In vivo studies for (R)-Lisofylline are typically conducted in rodent models of diabetes. A standard protocol for streptozotocin-treated rats involves administration of streptozotocin to induce diabetes, followed by treatment with (R)-Lisofylline (typically 10-50 mg/kg) by oral or intraperitoneal administration for several weeks. Oral glucose tolerance tests are performed to assess insulin response and glucose clearance. For NOD mouse studies, the compound is administered prophylactically or therapeutically, and the onset of diabetes is monitored by blood glucose measurements. Pancreatic tissues are collected for histopathological analysis of islet inflammation and macrophage infiltration.
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| ADME/Pharmacokinetics |
Metabolism / Metabolites
The known metabolites of lisoferine include pentoxifylline and lisoferine 4,5-diol. Pharmacokinetic data for (R)-Lisofylline is limited in the available literature. The compound's molecular weight is 280.32 g/mol. As a xanthine derivative, (R)-Lisofylline is expected to have reasonable oral bioavailability. The compound is metabolized by hepatic pathways, and its pharmacokinetic profile may differ from that of the parent compound Pentoxifylline. For in vivo studies, the compound is typically formulated in appropriate vehicles for oral or parenteral administration. Detailed PK parameters including half-life and clearance require empirical determination. |
| Toxicity/Toxicokinetics |
Toxicological data specific to (R)-Lisofylline is limited in the available literature. The compound is a research chemical and has been evaluated in preclinical studies for its safety profile. At therapeutic doses used in animal studies (10-50 mg/kg), the compound is generally well-tolerated. As with all xanthine derivatives, potential toxicity could include gastrointestinal effects and CNS stimulation at high doses. The compound's anti-inflammatory activities suggest it may have a favorable safety profile compared to other immunomodulatory agents. Standard laboratory safety precautions should be observed when handling this compound.
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| References |
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| Additional Infomation |
(R)-Lisoferrine is a 1-(5-hydroxyhexyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione with the (R)-configuration. It is a synthetic small molecule that was previously developed for the treatment of type 1 diabetes. It possesses anti-inflammatory and immunomodulatory effects. It is the enantiomer of (S)-Lisoferrine. Lisoferrine has been investigated for the treatment of type 1 diabetes.
(R)-Lisofylline is a research compound that has been investigated for potential therapeutic applications in diabetes and inflammatory diseases. As of the available information, the compound has not received regulatory approval for clinical use. It is commercially available from various suppliers for research purposes only. The compound's primary value lies in its utility as a pharmacological tool for studying the roles of LPAAT inhibition and anti-inflammatory mechanisms in diabetes and metabolic diseases. (R)-Lisofylline is the (R)-enantiomer of the Pentoxifylline metabolite and has been shown to enhance insulin response, lower glucose levels, and suppress IFN-γ production, making it a valuable tool for diabetes research. |
| Molecular Formula |
C13H20N4O3
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|---|---|
| Molecular Weight |
280.32
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| Exact Mass |
280.153
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| CAS # |
100324-81-0
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| Related CAS # |
(S)-Lisofylline;100324-80-9;(±)-Lisofylline;6493-06-7;(±)-Lisofylline-d6;1185995-26-9
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| PubChem CID |
501254
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
511.2±56.0 °C at 760 mmHg
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| Flash Point |
263.0±31.8 °C
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| Vapour Pressure |
0.0±1.4 mmHg at 25°C
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| Index of Refraction |
1.621
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| LogP |
0.34
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
20
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| Complexity |
390
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C[C@H](CCCCN1C(=O)C2=C(N=CN2C)N(C1=O)C)O
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| InChi Key |
NSMXQKNUPPXBRG-SECBINFHSA-N
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| InChi Code |
InChI=1S/C13H20N4O3/c1-9(18)6-4-5-7-17-12(19)10-11(14-8-15(10)2)16(3)13(17)20/h8-9,18H,4-7H2,1-3H3/t9-/m1/s1
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| Chemical Name |
1-[(5R)-5-hydroxyhexyl]-3,7-dimethylpurine-2,6-dione
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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 (e.g. under nitrogen), 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: 100 mg/mL (356.74 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 | 3.5674 mL | 17.8368 mL | 35.6735 mL | |
| 5 mM | 0.7135 mL | 3.5674 mL | 7.1347 mL | |
| 10 mM | 0.3567 mL | 1.7837 mL | 3.5674 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.
Link: https://clinicaltrials.gov/ct2/show/NCT04027192
Conditions:EndometriosisLink: https://clinicaltrials.gov/ct2/show/NCT01603121
Conditions:Type 1 Diabetes MellitusLink: https://clinicaltrials.gov/ct2/show/NCT00464555
Conditions:Type 1 Diabetes Mellitus
Title:Subcutaneous Administration of Lisofylline to Healthy Normal Subjects and Subjects With Type 1 Diabetes
Status:Completed
updateDate:2014-07-29
Ctid:NCT00896077
Link: https://clinicaltrials.gov/ct2/show/NCT00896077
Conditions:Healthy|Type 1 DiabetesProducts are for research use only; We do not sell to patients
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