| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
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| Other Sizes |
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| Targets |
cannabinoid receptor 1 (CB1)
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|---|---|
| ln Vitro |
A series of novel 3,4-diarylpyrazolines was synthesized and evaluated in cannabinoid (hCB(1) and hCB(2)) receptor assays. The 3,4-diarylpyrazolines elicited potent in vitro CB(1) antagonistic activities and in general exhibited high CB(1) vs CB(2) receptor subtype selectivities. [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.[Bioorg Med Chem Lett. 2012 Oct 1;22(19):6173-80.] |
| ln Vivo |
Some key representatives showed potent pharmacological in vivo activities after oral dosing in both a CB agonist-induced blood pressure model and a CB agonist-induced hypothermia model. Chiral separation of racemic 67, followed by crystallization and an X-ray diffraction study, elucidated the absolute configuration of the eutomer 80 (SLV319) at its C(4) position as 4S. Bioanalytical studies revealed a high CNS-plasma ratio for the development candidate 80. Molecular modeling studies showed a relatively close three-dimensional structural overlap between 80 and the known CB(1) receptor antagonist rimonabant (SR141716A). Further analysis of the X-ray diffraction data of 80 revealed the presence of an intramolecular hydrogen bond that was confirmed by computational methods. Computational models and X-ray diffraction data indicated a different intramolecular hydrogen bonding pattern in the in vivo inactive compound 6. In addition, X-ray diffraction studies of 6 revealed a tighter intermolecular packing than 80, which also may contribute to its poorer absorption in vivo. Replacement of the amidine -NH(2) moiety with a -NHCH(3) group proved to be the key change for gaining oral biovailability in this series of compounds leading to the identification of 80 [1].
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| Enzyme Assay |
Receptor Binding Assays.[2]
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. [2] 2. CB2 Assay. [2] 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.[2] |
| 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[2].
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| References | |
| Additional Infomation |
The lead optimization of the CB1 cannabinoid receptor antagonist 5 has led to the development candidates 78 (SLV326) and 80. Both 78 and 80 are novel subtype selective CB1 receptor antagonists exhibiting potent pharmacological activity in vitro as well as in vivo after oral administration. It has been demonstrated that the interactions of the enantiomers 78−81 with the CB1 receptor are highly stereoselective. Mono- and dimethylation of the polar carboxamidine moiety in 6 resulted in the compounds 80 and 25 having substantially lower calculated PSA values. These methylations are pivotal in governing the oral bioavailability in the pyrazoline series, conceivably by subtly affecting the degree of dissolution rate in the gastrointestinal tract, as the result of a different intramolecular hydrogen bonding pattern and crystal packing.[1]
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| Molecular Formula |
C23H20N4O2SCL2
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|---|---|
| Molecular Weight |
487.4015
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| Exact Mass |
486.068
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| Elemental Analysis |
C, 56.68; H, 4.14; Cl, 14.55; N, 11.50; O, 6.57; S, 6.58
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| CAS # |
656827-86-0
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| Related CAS # |
464213-10-3 (S-isomer)； 656827-86-0 (R-isomer); 362519-49-1 (racemate)
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| PubChem CID |
11363773
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
623.2±65.0 °C at 760 mmHg
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| Flash Point |
330.7±34.3 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.663
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| LogP |
4.67
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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 |
6
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| Heavy Atom Count |
32
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| Complexity |
791
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| Defined Atom Stereocenter Count |
1
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| 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
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| InChi Key |
AXJQVVLKUYCICH-NRFANRHFSA-N
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| 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-/m0/s1
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| Chemical Name |
(4R)-5-(4-chlorophenyl)-N-(4-chlorophenyl)sulfonyl-N'-methyl-4-phenyl-3,4-dihydropyrazole-2-carboximidamide
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| Synonyms |
(R)-SLV 319; (R)-SLV-319; S-Ibipinabant; Ibipinabant S-isomer
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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) |
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
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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 | 2.0517 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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