|
Otenabant HCl (also known as CP-945,598; CP 945,598; CP-945598), the hydrochloride salt of Otenabant, is a novel, potent and highly selective cannabinoid receptor CB1 antagonist with potential anti-obesity effect. It exhibits >10,000-fold higher selectivity against CB2 receptor and inhibits CB1 with a Ki of 0.7 nM. Pfizer developed otenabant with the intention of treating obesity; however, the drug's development has been shelved because of issues with rimonabant, a comparable medication, during clinical trials.
|
Physicochemical Properties
| Molecular Formula |
C25H26CL3N7O
|
| Molecular Weight |
546.88
|
| Exact Mass |
545.126
|
| Elemental Analysis |
C, 54.91; H, 4.79; Cl, 19.45; N, 17.93; O, 2.93
|
| CAS # |
686347-12-6
|
| Related CAS # |
Otenabant; 686344-29-6
|
| PubChem CID |
16223963
|
| Appearance |
White solid powder
|
| Melting Point |
275-276℃ (decomposition)
|
| LogP |
6.181
|
| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
36
|
| Complexity |
729
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
[H]Cl.ClC1=CC=CC=C1C2=NC3=C(N4CCC(NCC)(C(N)=O)CC4)N=CN=C3N2C5=CC=C(Cl)C=C5
|
| InChi Key |
KPYUQCJBZGQHPL-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C25H25Cl2N7O.ClH/c1-2-31-25(24(28)35)11-13-33(14-12-25)22-20-23(30-15-29-22)34(17-9-7-16(26)8-10-17)21(32-20)18-5-3-4-6-19(18)27;/h3-10,15,31H,2,11-14H2,1H3,(H2,28,35);1H
|
| Chemical Name |
1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)purin-6-yl]-4-(ethylamino)piperidine-4-carboxamide;hydrochloride
|
| Synonyms |
| CP-945,598; CP 945,598; CP-945598; Otenabant HCl; CP945598; CP 945598; CP945,598 |
|
| 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)
|
|
Biological Activity
| Targets |
hCB1 ( Ki = 0.7 nM ); rCB1 ( Ki = 2.8 nM )
|
| ln Vitro |
In vitro activity: Otenabant HCl has a low affinity for human CB2 receptors, with a Ki of 7.6 μM[1]. Otenabant HCl inhibits the CB1 receptor with low hERG affinity, sufficient CNS penetration, and moderate unbound microsomal clearance[2]. |
|
| ln Vivo |
| Otenabant causes a metabolic shift toward greater fat oxidation by sharply increasing energy expenditure and lowering the respiratory quotient in rats. In a 10-day weight loss study, diet-induced obese mice treated with otenabant (10 mg/kg, p.o.) showed a 9% vehicle adjusted weight loss[1]. After administering the synthetic CB1 receptor agonist CP-55940, tenabant HCl reverses four behaviors mediated by cannabinoids: locomotor activity, hypothermia, analgesia, and catalepsy. Otenabant HCl increases energy expenditure and fat oxidation in a rodent model of acute food intake and demonstrates dose-dependent anorectic activity[2]. |
|
| Enzyme Assay |
Membranes are made from CHOK1 cells that have had the human CB-1 receptor cDNA transfected into them permanently. The GTPγ [35S] binding assays are carried out in duplicate in a 96-well FlashPlate format using 100 pM GTPγ [35S] and 10μg membrane per well in an assay buffer consisting of 50 mM Tris HCl, pH 7.4, 3 mM MgCl2, pH 7.4, 10 mM MgCl2, 20 mM EGTA, 100 mM NaCl, 30 µM GDP, 0.1% bovine serum albumin, and the protease inhibitors 100 μg/mL bacitracin, 100 μg/mL benzamidine, 5 μg/mL aprotinin, and 5 μg/mL leupeptin. After 10 minutes of incubation with escalating antagonist concentrations (10-10M to 10-5 M), the assay mix is challenged with the cannabinoid agonist CP-55,940 (10 μM). For one hour, assays are conducted at 30°C. The FlashPlates are subsequently centrifuged for 10 minutes at 2000 g. Next, utilizing a Wallac Microbeta, the stimulation of GTPγ [35S] binding is measured. GraphPad Prism is used to calculate EC50. The absence of an agonist is used to measure inverse agonism.
|
| Animal Protocol |
| The 14-week-old male C57/Bl6/6J mice were chosen for the DIO weight loss study after they were fed a high-fat diet (45% kcal from fat) for six weeks. The age-matched, chow-fed control animals' mean body weight is at least five standard deviations out of the range for the animal weights. Mouse housing is done in pairs. All animals weigh 38.9±0.5 g on average when they first start. Day 0: Treatment groups (n = 10 per group) are randomly assigned to mice. Over ten days, mice are given a daily dose of either vehicle or 10 mg/kg (p.o.) CP-945,598. The dosing occurs roughly half an hour before the start of the 12-hour dark cycle. Food consumption and BW are tracked every day. Daily and cumulative FI and cumulative BW measurements are computed along with an analysis of variance and a comparison of means. Statistical significance is defined as P < 0.05. | |
|
| References |
[1]. In vitro and in vivo pharmacology of CP-945,598, a potent and selective cannabinoid CB1 receptor antagonist for the management of obesity. Biochemical and Biophysical Research Communications, 2010; 394;366-371.
[2]. Discovery of 1-[9-(4-chlorophenyl) -8-(2-chlorophenyl)- 9H-purin-6-yl] -4-ethylaminopiperidine-4-carboxylic acid amide hydrochloride (CP-945,598), a novel, potent, and selective cannabinoid type 1 receptor antagonist. J. Med. Chem. 2009, 52, 2, 234–237.
|
|
Solubility Data
| Solubility (In Vitro) |
| DMSO: 1~5 mg/mL (1.8~9.1 mM) | | Water: <1 mg/mL | | Ethanol: <1 mg/mL |
|
| Solubility (In Vivo) |
| 0.5% methylcellulose: 17 mg/mL |
(Please use freshly prepared in vivo formulations for optimal results.)
|
| Preparing Stock Solutions |
|
1 mg |
5 mg |
10 mg |
| 1 mM |
1.8286 mL |
9.1428 mL |
18.2855 mL |
| 5 mM |
0.3657 mL |
1.8286 mL |
3.6571 mL |
| 10 mM |
0.1829 mL |
0.9143 mL |
1.8286 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. |
 HCl Chemical Structure.png)