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Rimonabant (also known as SR141716, SR-141716A; A 281) is a novel, potent and selective antagonist (inverse agonist) of cannabinoid CB1 receptor with IC50 of 13.6 nM and EC50 of 17.3 nM in hCB1 transfected HEK 293 membrane. Rimonabant is used as an anorectic anti-obesity drug. Its principal impact is appetite suppression. A 285-fold CB1 selectivity has been demonstrated by rimonabant (Ki=1.8nM CB1, 514nM CB2). The affinity of Rimonabant for CB1-Rs is 50-fold higher than for CB2-Rs with a Ki value of 6.18nM for CB1-Rs. Furthermore, it has been demonstrated that rimonabant, when used as a treatment alone, alters ingestive behaviors.
Physicochemical Properties
| Molecular Formula | C22H22CL4N4O | |
| Molecular Weight | 500.25 | |
| Exact Mass | 498.054 | |
| Elemental Analysis | C, 52.82; H, 4.43; Cl, 28.35; N, 11.20; O, 3.20 | |
| CAS # | 158681-13-1 | |
| Related CAS # | Rimonabant; 168273-06-1; Rimonabant-d10 hydrochloride; 1044909-61-6 | |
| PubChem CID | 104850 | |
| Appearance | White to off-white solid powder | |
| Boiling Point | 627.6ºC at 760 mmHg | |
| Melting Point | 230-240ºC | |
| Flash Point | 333.3ºC | |
| LogP | 7.069 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 3 | |
| Rotatable Bond Count | 4 | |
| Heavy Atom Count | 30 | |
| Complexity | 583 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | ClC1C([H])=C(C([H])=C([H])C=1N1C(C2C([H])=C([H])C(=C([H])C=2[H])Cl)=C(C([H])([H])[H])C(C(N([H])N2C([H])([H])C([H])([H])C([H])([H])C([H])([H])C2([H])[H])=O)=N1)Cl.Cl[H] |
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| InChi Key | REOYOKXLUFHOBV-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C22H21Cl3N4O.ClH/c1-14-20(22(30)27-28-11-3-2-4-12-28)26-29(19-10-9-17(24)13-18(19)25)21(14)15-5-7-16(23)8-6-15;/h5-10,13H,2-4,11-12H2,1H3,(H,27,30);1H | |
| Chemical Name | 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-piperidin-1-ylpyrazole-3-carboxamide;hydrochloride | |
| Synonyms |
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| 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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | CB1 ( Ki = 1.8 nM ) | ||
| ln Vitro |
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| ln Vivo |
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| Enzyme Assay | Human CB1 and CB2 purify the cell membrane and transfect HEK 293 cells in a stable manner. In the incubation buffer (50 mM Tris-HCl, 5 mM MgCl2, 1 mM EDTA, 0.3% BSA, pH 7.4), 0.2–8 μg of the purified membrane are incubated with 0.75 nM [3H] CP55,940 and Rimonabant. In the presence of 1 μM of CP55,940, the non-specific binding is defined. The reactions are incubated in Multiscreen at 30 °C for one and a half hours. After four rounds of ice-cold wash buffer (50 mM Tris, pH 7.4, 0.25% BSA), the reactions are stopped by manifold filtration. With Topcount, the radioactivity bound to the filters is measured. The IC50 is computed using non-linear regression and is defined as the concentration of rimonabant needed to inhibit 50% of the binding of [3H] CP55,940. | ||
| Cell Assay | Raw 264.7 after rinsing 12-well plates with PBS, cells (2 × 106/well) are refed with culture media supplemented with different amounts of Rimonabant one hour before 7-ketocholesterol (7KC) are added. The amount of vehicle is adjusted so that each well receives the same amount. A fluorogenic substrate (ac-DEVD-AFC) and a spectrofluorometer fitted with a microplate reader are used to measure caspase-3 and caspase 3-like activity after a 16-hour incubation. | ||
| Animal Protocol |
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Undetermined Metabolism / Metabolites Hepatic, CYP3A4 involved. Biological Half-Life 6 to 9 days with normal BMI and 16 days if BMI is greater than 30 |
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| Toxicity/Toxicokinetics |
Protein Binding Almost 100% |
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| References |
[1]. FEBS Lett. 1994 Aug 22;350(2-3):240-4. [2]. FInt J Cancer. 2009 Sep 1;125(5):996-1003. [3]. Neural Plast. 2016;2016:6481862. |
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| Additional Infomation |
Rimonabant is a carbohydrazide obtained by formal condensation of the carboxy group of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid with the amino group of 1-aminopiperidine. It is a potent and selective cannabinoid receptor 1 (CB1R) antagonist. Besides its antagonistic properties, numerous studies have shown that, at micromolar concentrations rimonabant behaves as an inverse agonist at CB1 receptors. The drug was the first selective CB1 antagonist/inverse agonist introduced into clinical practice to treat obesity and metabolic-related disorders. It was later withdrawn from market due to CNS-related adverse effects including depression and suicidal ideation. It has a role as an anti-obesity agent, a CB1 receptor antagonist and an appetite depressant. It is a member of pyrazoles, a dichlorobenzene, a carbohydrazide, an amidopiperidine and a member of monochlorobenzenes. Rimonabant is an anorectic anti-obesity drug produced and marketed by Sanofi-Aventis. It is an inverse agonist for the cannabinoid receptor CB1. Its main avenue of effect is reduction in appetite. Rimonabant is the first selective CB1 receptor blocker to be approved for use anywhere in the world. Rimonabant is approved in 38 countries including the E.U., Mexico, and Brazil. It was rejected for approval for use in the United States. This decision was made after a U.S. advisory panel recommended the medicine not be approved because it may increase suicidal thinking and depression. A pyrazole and piperidine derivative that acts as a selective cannabinoid type-1 receptor (CB1 RECEPTOR) antagonist. It inhibits the proliferation and maturation of ADIPOCYTES, improves lipid and glucose metabolism, and regulates food intake and energy balance. It is used in the management of OBESITY. Drug Indication For use in conjunction with diet and exercise for patients with a body mass index greater than 30 kg/m2, or patients wih a BMI greater than 27 kg/m2 with associated risk factors, such as type 2 diabetes or dyslipidaemia. As an adjunct to diet and exercise for the treatment of obese patients (BMI 30 kg/m2), or overweight patients (BMI 27 kg/m2) with associated risk factor(s), such as type 2 diabetes or dyslipidaemia (see section 5. 1). As an adjunct to diet and exercise for the treatment of obese patients (BMI 30 kg/m2), or overweight patients (BMI 27 kg/m2) with associated risk factor(s), such as type 2 diabetes or dyslipidaemia (see section 5. 1). Mechanism of Action Rimonabant is a specific CB1 cannabinoid receptor antagonist. There is considerable evidence that the endocannabinoid (endogenous cannabinoid) system plays a significant role in appetitive drive and associated behaviours. It is therefore reasonable to hypothesize that the attenuation of the activity of this system would have therapeutic benefit in treating disorders that might have a component of excess appetitive drive or over-activity of the endocannabinoid system, such as obesity, ethanol and other drug abuse, and a variety of central nervous system and other disorders. Pharmacodynamics In the RIO-North America trial, 3040 patients were randomized to receive either placebo or one of two doses of rimonabant (5 mg or 20 mg per day). Patients taking 20 mg rimonabant had significant weigh loss, decrease in waist circumference, improved insulin sensitivity, and increases in HDL cholesterol, compared to patients on placebo. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (5.00 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.00 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 3: 30% PEG400+0.5% Tween80+5% Propylene glycol : 30 mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9990 mL | 9.9950 mL | 19.9900 mL | |
| 5 mM | 0.3998 mL | 1.9990 mL | 3.9980 mL | |
| 10 mM | 0.1999 mL | 0.9995 mL | 1.9990 mL |