| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
CB1 7.8 nM (Ki) CB2 7943 nM (Ki)
|
|---|---|
| ln Vitro |
With a Ki of 7.8 nM, SLV319 displaces the particular CP-55940 (CB agonist) binding in CHO cells that have been transfected with the human CB1 receptor in a stable manner[1]. With a pA2 of 9.9, SLV319 concentration-dependently inhibits the production of arachidonic acid in CHO cells stimulated by WIN-55212 (a CB1 agonist)[1].
Analogs of SLV-319 (Ibipinibant), a CB1 receptor inverse agonist, were synthesized with functionality intended to limit brain exposure while maintaining the receptor affinity and selectivity of the parent compound. Structure activity relationships of this series, and pharmacology of two lead compounds, 16 (JD-5006) and 23 (JD-5037) showing little brain presence as indicated by tissue distribution and receptor occupancy studies, are described. Effects with one of these compounds on plasma triglyceride levels, liver weight and enzymes, glucose tolerance and insulin sensitivity support the approach that blockade of peripheral CB(1) receptors is sufficient to produce many of the beneficial metabolic effects of globally active CB(1) blockers. Thus, PR CB(1) inverse agonists may indeed represent a safer alternative to highly brain-penetrant agents for the treatment of metabolic disorders, including diabetes, liver diseases, dyslipidemias, and obesity.[1] |
| ln Vivo |
In diet-induced obesity (DIO) mice, SLV319 (3 mg/kg/day; po for 28 d) decreases food intake, body weight, and hormonal/metabolic abnormalities[2]. SLV319 (3 mg/kg/day, po for 28 days) counteracts the rise in adipose tissue leptin mRNA that is brought on by a high fat diet[2]. In a rat model of progressive β-cell failure, SLV319 (3–10 mg/kg; daily oral gavage for 56 days) attenuates β-cell loss and has weight loss-independent antidiabetic effects[3]. With an ED50 of 5.5 and 3 mg/kg, respectively, SLV319 (oral dosing) counteracts CB agonist (CP55940)-induced hypotension in rats and hypothermia in mice[1].
At the end of the study, vehicle-treated ZDF rats were severely hyperglycaemic and showed signs of β-cell decline, including dramatic reductions in unfasted insulin levels. Ibipinanbant (10 mg/kg) reduced the following relative to vehicle controls: fasting glucose (-61%), glucose excursion area under the curve (AUC) in an oral glucose tolerance test (OGTT, -44%) and HbA1c (-50%). Furthermore, non-fasting insulin, islet area and islet insulin content were all increased (71, 40 and 76%, respectively) relative to vehicle controls by the end of the study. All of these effects were similar to those of rimonabant and rosiglitazone, where ibipinabant was slightly more effective than rimonabant at the lowest dose and somewhat less effective than rosiglitazone at all doses. These antidiabetic effects appear independent of weight loss because none of the parameters above were consistently improved by the comparable weight loss induced by food restriction. Conclusions: Ibipinabant may have weight loss-independent antidiabetic effects and may have the potential to attenuate β-cell loss in a model of progressive β-cell dysfunction [3]. |
| Enzyme Assay |
Receptor Binding Assays.[1]
1. CB1 Assay. CB1 receptor affinities were determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid CB1 receptor is stably transfected in conjunction with [3H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [3H]-radioligand, with or without addition of test compound, separation of bound and free ligand was performed by filtration over glassfiber filters. Radioactivity on the filter was measured by liquid scintillation counting. The IC50 values from at least three independent measurements were combined and converted to Ki values using the assumptions of Cheng and Prusoff. [1] 2. CB2 Assay. [1] CB2 receptor affinities were determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid CB2 receptor is stably transfected20 in conjunction with [3H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [3H]-radioligand, with or without addition of test compound, separation of bound and free ligand was performed by filtration over glassfiber filters. Radioactivity on the filter was measured by liquid scintillation counting. The IC50 values from at least two independent measurements were combined and converted to Ki values using the assumptions of Cheng and Prusoff.[1] |
| Cell Assay |
In Vitro Pharmacology. Measurement of Arachidonic Acid Release. CB1 receptor antagonism21 was assessed with the human CB1 receptor cloned in Chinese hamster ovary (CHO) cells. CHO cells were grown in a Dulbecco's modified Eagle's medium (DMEM) culture medium, supplemented with 10% heat-inactivated fetal calf serum. Medium was aspirated and replaced by DMEM, without fetal calf serum, but containing [3H]-arachidonic acid and incubated overnight in a cell culture stove (5% CO2/95% air; 37 °C; water-saturated atmosphere). During this period [3H]-arachidonic acid was incorporated in membrane phospholipids. On the test day, medium was aspirated and cells were washed three times using 0.5 mL of DMEM, containing 0.2% bovine serum albumin (BSA). Stimulation of the CB1 receptor by WIN 55,212-2 led to activation of PLA2 followed by release21 of [3H]-arachidonic acid into the medium. This WIN 55,212-2-induced release was concentration dependently antagonized by CB1 receptor antagonists. The CB1 antagonistic potencies of the test compounds were expressed as pA2 values[1].
|
| Animal Protocol |
Animal/Disease Models: Sixweeks old male C57Bl/6J mice received a diet containing 60% of calories as fat, resulting in body weights >42 g in 12-14 weeks[2]
Doses: 3 mg/kg/day Route of Administration: Po for 28 days Experimental Results: Caused reductions in food intake, body weight and adiposity in DIO mice. |
| References |
|
| Additional Infomation |
SLV319 belongs to a novel class of agents called CB1 antagonists, which work by blocking the cannabinoid type 1 (CB1) receptor. It is developed for the treatment of obesity and other metabolic disorders.
Ibipinabant has been used in trials studying the treatment of Obesity and Obesity and Type 2 Diabetes. Drug Indication Investigated for use/treatment in obesity. Mechanism of Action SLV319 belongs to a novel class of agents called CB1 antagonists, which work by blocking the cannabinoid type 1 (CB1) receptor. Clinical and preclinical studies involving this class of drug have shown that blocking the cannabinoid type 1 (CB1) receptor results in reduced food intake.. |
| Molecular Formula |
C23H20CL2N4O2S
|
|---|---|
| Molecular Weight |
487.4015
|
| Exact Mass |
486.068
|
| Elemental Analysis |
C, 56.68; H, 4.14; Cl, 14.55; N, 11.50; O, 6.57; S, 6.58
|
| CAS # |
464213-10-3
|
| Related CAS # |
(±)-Ibipinabant;362519-49-1; 464213-10-3 (S-isomer)； 656827-86-0 (R-isomer)
|
| PubChem CID |
9826744
|
| Appearance |
White to off-white solid powder
|
| Density |
1.4±0.1 g/cm3
|
| Boiling Point |
623.2±65.0 °C at 760 mmHg
|
| Flash Point |
330.7±34.3 °C
|
| Vapour Pressure |
0.0±1.8 mmHg at 25°C
|
| Index of Refraction |
1.663
|
| LogP |
4.67
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
4
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
32
|
| Complexity |
791
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
CN=C(NS(=O)(=O)C1=CC=C(C=C1)Cl)N2C[C@H](C3=CC=CC=C3)C(=N2)C4=CC=C(C=C4)Cl
|
| InChi Key |
AXJQVVLKUYCICH-OAQYLSRUSA-N
|
| InChi Code |
InChI=1S/C23H20Cl2N4O2S/c1-26-23(28-32(30,31)20-13-11-19(25)12-14-20)29-15-21(16-5-3-2-4-6-16)22(27-29)17-7-9-18(24)10-8-17/h2-14,21H,15H2,1H3,(H,26,28)/t21-/m1/s1
|
| Chemical Name |
(4S)-5-(4-chlorophenyl)-N-(4-chlorophenyl)sulfonyl-N'-methyl-4-phenyl-3,4-dihydropyrazole-2-carboximidamide
|
| Synonyms |
Ibipinabant (SLV319) S-isomer
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
|
|---|---|
| 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 | 2.0517 mL | 10.2585 mL | 20.5170 mL | |
| 5 mM | 0.4103 mL | 2.0517 mL | 4.1034 mL | |
| 10 mM | 0.2052 mL | 1.0259 mL | 2.0517 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 |
| NCT00541567 | Completed | Drug: ibipinabant | Obesity and Type 2 Diabetes | Solvay Pharmaceuticals | March 2008 | Phase 2 Phase 3 |
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