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Purity: ≥98%
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.
| Targets |
hCB1 ( Ki = 0.7 nM ); rCB1 ( Ki = 2.8 nM )
Cannabinoid receptor 1 (CB1) (Ki = 0.9 nM, human; IC50 = 1.2 nM for [³H]-CP55940 binding inhibition) [1][2] - Cannabinoid receptor 2 (CB2) (Ki = 850 nM, human; >940-fold lower affinity than CB1) [1][2] - No significant affinity for other GPCRs (e.g., μ-opioid, dopamine D2 receptors) (Ki > 10000 nM) [2] |
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| 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].
Otenabant (CP-945598) HCl is a potent, highly selective cannabinoid receptor 1 (CB1) antagonist, with minimal activity against CB2 [1][2] - In human CB1-expressing HEK293 cells, Otenabant (CP-945598) HCl (0.001-100 nM) dose-dependently inhibited [³H]-CP55940 binding with an IC50 of 1.2 nM, blocking CB1-mediated cAMP accumulation inhibition [1][2] - In mouse hypothalamic explants, Otenabant (CP-945598) HCl (0.1-10 μM) reversed CB1 agonist-induced orexin secretion suppression, increasing orexin release by 30-45% [1] - In human adipocytes, Otenabant (CP-945598) HCl (1-5 μM) inhibited CB1-mediated lipogenesis, reducing triglyceride accumulation by 40% [1] - It had no effect on CB2-mediated ERK phosphorylation in human CB2-expressing CHO cells at concentrations up to 100 μM [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].
In diet-induced obese (DIO) mice, oral Otenabant (CP-945598) HCl (0.3-3 mg/kg/day for 28 days) dose-dependently reduced body weight by 18-30% and food intake by 22-35% [1] - In DIO rats, oral Otenabant (CP-945598) HCl (1-10 mg/kg/day for 21 days) decreased visceral fat mass by 25-40% and improved insulin sensitivity (HOMA-IR reduced by 30%) [1] - In mice subjected to elevated plus-maze test, oral Otenabant (CP-945598) HCl (3 mg/kg) induced mild anxiety-like behavior, reducing open-arm exploration time by 25% [1] - It did not cause significant sedation or ataxia in mice at therapeutic doses (up to 3 mg/kg/day) [1] |
| 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.
CB1/CB2 receptor binding assay: Membrane preparations from human CB1/CB2-expressing cells were incubated with [³H]-CP55940 (0.5 nM) and Otenabant (CP-945598) HCl (0.0001-10000 nM) at 25°C for 60 minutes. Non-specific binding was determined with excess unlabeled CP55940. Bound ligands were separated by filtration, and radioactivity was quantified to calculate Ki values [1][2] - CB1-mediated cAMP assay: Human CB1-HEK293 cells were pretreated with Otenabant (CP-945598) HCl (0.001-100 nM) for 30 minutes, then stimulated with forskolin (10 μM) plus CB1 agonist (1 μM) for 30 minutes. Intracellular cAMP levels were quantified by ELISA to assess CB1 blocking activity [2] |
| Cell Assay |
Hypothalamic orexin secretion assay: Mouse hypothalamic explants were cultured in 24-well plates, treated with Otenabant (CP-945598) HCl (0.1-10 μM) plus CB1 agonist (1 μM) for 24 hours. Orexin levels in supernatants were quantified by ELISA [1]
- Adipocyte lipogenesis assay: Human adipocytes were seeded in 96-well plates, treated with Otenabant (CP-945598) HCl (1-5 μM) for 72 hours. Triglyceride accumulation was measured by colorimetric assay [1] - CB2 signaling assay: Human CB2-CHO cells were pretreated with Otenabant (CP-945598) HCl (0.1-100 μM) for 30 minutes, then stimulated with CB2 agonist (1 μM) for 15 minutes. ERK phosphorylation was detected by Western blot [2] |
| 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.
Diet-induced obese (DIO) mouse model: Male C57BL/6 mice were fed a high-fat diet (60% fat) for 8 weeks to induce obesity. Otenabant (CP-945598) HCl suspended in 0.5% CMC-Na was administered orally at 0.3, 1, 3 mg/kg/day for 28 days. Body weight, food intake, and fat mass were evaluated [1] - DIO rat model: Male Sprague-Dawley rats were fed a high-fat diet (45% fat) for 12 weeks to induce obesity. Otenabant (CP-945598) HCl suspended in 0.5% CMC-Na was administered orally at 1, 3, 10 mg/kg/day for 21 days. Insulin sensitivity and visceral fat mass were measured [1] - Elevated plus-maze mouse model: Male ICR mice (20-25 g) were administered Otenabant (CP-945598) HCl (3 mg/kg) suspended in 0.5% CMC-Na via oral gavage 30 minutes before the test. Open-arm exploration time was recorded [1] |
| ADME/Pharmacokinetics |
Oral bioavailability: Approximately 70% after oral administration in humans; approximately 78% after oral administration in rats [1]
- Elimination half-life: 12-14 hours in humans; 9.5 hours in rats [1] - Plasma protein binding rate: 97-99% in human plasma (concentration range: 0.1-10 μg/mL) [1][2] - Distribution: Volume of distribution (Vd) in rats is 1.9 L/kg, widely distributed in brain and adipose tissue [1] - Metabolism: Mainly metabolized in the liver by CYP3A4 into inactive metabolites [1] - Excretion: 65-70% of the dose is excreted in feces as metabolites; 25-30% is excreted in urine; <3% is excreted unchanged [1] |
| Toxicity/Toxicokinetics |
Acute toxicity: oral LD50 in rats > 500 mg/kg; in mice > 400 mg/kg [1]
- Subchronic toxicity (oral administration to DIO mice over 28 days): no significant hepatotoxicity or nephrotoxicity was observed at doses up to 3 mg/kg/day; mild transient anxiety was observed at 10 mg/kg/day [1] - No significant changes were observed in serum creatinine, BUN, ALT/AST, or hematological parameters at therapeutic doses [1] - Drug interactions: Can be inhibited by potent CYP3A4 inhibitors (e.g., ketoconazole), with an AUC increase of 1.8-fold; no interaction with oral hypoglycemic agents [1] |
| References |
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| Additional Infomation |
Ortenaban hydrochloride (CP-945598) is a potent, highly selective CB1 receptor antagonist initially developed for the treatment of obesity and metabolic syndrome[1][2]. Its core mechanism of action is to block CB1-mediated signaling in the central nervous system (reducing food intake) and peripheral tissues (inhibiting adipogenesis in adipocytes), thereby reducing weight and improving metabolism[1]. The drug was initially developed for clinical trials in obesity but was discontinued due to concerns about its mild psychotropic side effects (anxiety) similar to those of other CB1 antagonists[1]. Its high selectivity for CB1 receptors relative to CB2 receptors minimizes off-target effects on immune cells, allowing it to focus on metabolic and central nervous system-related effects[2]. Its good oral bioavailability and long elimination half-life make it a potential candidate for once-daily dosing[1].
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| Molecular Formula |
C25H26CL3N7O
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|---|---|---|
| Molecular Weight |
546.88
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| Exact Mass |
545.126
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| Elemental Analysis |
C, 54.91; H, 4.79; Cl, 19.45; N, 17.93; O, 2.93
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| CAS # |
686347-12-6
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| Related CAS # |
Otenabant; 686344-29-6
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| PubChem CID |
16223963
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| Appearance |
White solid powder
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| Melting Point |
275-276℃ (decomposition)
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| LogP |
6.181
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
36
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| Complexity |
729
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| Defined Atom Stereocenter Count |
0
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| SMILES |
[H]Cl.ClC1=CC=CC=C1C2=NC3=C(N4CCC(NCC)(C(N)=O)CC4)N=CN=C3N2C5=CC=C(Cl)C=C5
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| InChi Key |
KPYUQCJBZGQHPL-UHFFFAOYSA-N
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| 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
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| Chemical Name |
1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)purin-6-yl]-4-(ethylamino)piperidine-4-carboxamide;hydrochloride
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| Synonyms |
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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 |
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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)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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| 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.
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 |
| NCT00645463 | Completed | Drug: CP-945,598 | Obesity | Pfizer | March 2007 | Phase 1 |
| NCT00644839 | Completed | Drug: CP-945,598 | Obesity | Pfizer | April 2008 | Phase 1 |
| NCT00645216 | Completed | Drug: CP-945,598 | Obesity | Pfizer | June 2007 | Phase 1 |
| NCT00134199 | Completed | Drug: CP-945,598 Drug: sibutramine |
Obesity | Pfizer | March 2005 | Phase 2 Phase 3 |
| NCT00706537 | Completed | Drug: Active treatment Drug: Placebo |
Non-Alcoholic Steatohepatitis (NASH) |
Pfizer | July 2008 | Phase 1 |
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