Update on Rimonabant—A Selective Cannabinoid CB1 Antagonist

Boyd, Steven T.; Fremming, Brad Allen

doi:10.1345/aph.1g713

Cited by 5 publications

(4 citation statements)

References 3 publications

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“…32,33 Rimonabant was approved in 2006 for the treatment of obesity but was withdrawn in 2008 due to serious drug-related psychiatric disorders, including anxiety and depression. 34,35 The structure of rimonabant is given in Figure 1.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Rimonabant is an N-acylaminopiperidinyl derivative with cannabinoid type 1 receptor (CB1r) antagonist properties that has been reported to be effective in appetite control and smoking cessation therapy. 32,33 Rimonabant was approved in 2006 for the treatment of obesity but was withdrawn in 2008 due to serious drug-related psychiatric disorders, including anxiety and depression. 34,35 The structure of rimonabant is given in Figure 1.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Rimonabant is an N -acylaminopiperidinyl derivative with cannabinoid type 1 receptor (CB1r) antagonist properties that has been reported to be effective in appetite control and smoking cessation therapy. , Rimonabant was approved in 2006 for the treatment of obesity but was withdrawn in 2008 due to serious drug-related psychiatric disorders, including anxiety and depression. , The structure of rimonabant is given in Figure . Biotransformation studies of rimonabant in vitro in rat and human liver microsomes (HLM) have revealed high levels of reactive metabolite formation and NADPH dependent CVB to microsomal proteins .…”

Section: Introductionmentioning

confidence: 99%

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Use of Electrochemical Oxidation and Model Peptides To Study Nucleophilic Biological Targets of Reactive Metabolites: The Case of Rimonabant

Thorsell

Isin

Jurva

2014

Chem. Res. Toxicol.

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Electrochemical oxidation of drug molecules is a useful tool to generate several different types of metabolites. In the present study we developed a model system involving electrochemical oxidation followed by characterization of the oxidation products and their propensity to modify peptides. The CB1 antagonist rimonabant was chosen as the model drug. Rimonabant has previously been shown to give high covalent binding to proteins in human liver microsomes and hepatocytes and the iminium ion and/or the corresponding aminoaldehyde formed via P450 mediated α-carbon oxidation of rimonabant was proposed to be a likely contributor. This proposal was based on the observation that levels of covalent binding were significantly reduced when iminium species were trapped as cyanide adducts but also following addition of methoxylamine expected to trap aldehydes. Incubation of electrochemically oxidized rimonabant with peptides resulted in peptide adducts to the N-terminal amine with a mass increment of 64 Da. The adducts were shown to contain an addition of C5H4 originating from the aminopiperidine moiety of rimonabant. Formation of the peptide adducts required further oxidation of the iminium ion to short-lived intermediates, such as dihydropyridinium species. In addition, the metabolites and peptide adducts generated in human liver microsomes were compared with those generated by electrochemistry. Interestingly, the same peptide modification was found when rimonabant was coincubated with one of the model peptides in microsomes. This clearly indicated that reactive metabolite(s) of rimonabant identical to electrochemically generated species are also present in the microsomal incubations. In summary, electrochemical oxidation combined with peptide trapping of reactive metabolites identified a previously unobserved bioactivation pathway of rimonabant that was not captured by traditional trapping agents and that may contribute to the in vitro covalent binding.

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Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

“…Rimonabant is an N -acylaminopiperidinyl derivative with cannabinoid type 1 receptor (CB1r) antagonist properties that has been reported to be effective in appetite control and smoking cessation therapy. , Rimonabant was approved in 2006 for the treatment of obesity but was withdrawn in 2008 due to serious drug-related psychiatric disorders, including anxiety and depression. , The structure of rimonabant is given in Figure . Biotransformation studies of rimonabant in vitro in rat and human liver microsomes (HLM) have revealed high levels of reactive metabolite formation and NADPH dependent CVB to microsomal proteins .…”

Section: Introductionmentioning

confidence: 99%

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Use of Electrochemical Oxidation and Model Peptides To Study Nucleophilic Biological Targets of Reactive Metabolites: The Case of Rimonabant

Thorsell

Isin

Jurva

2014

Chem. Res. Toxicol.

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“…Rimonabant (Acomplia, 1 ) was the first of a new class of selective cannabinoid type 1 receptor (CB1r) antagonists and was developed as an appetite suppressant to manage obesity and associated cardiovascular risk factors. , When administered to overweight and obese patients at a dose of 20 mg/day, rimonabant was reported to reduce the overactivity of the endocannabinoid system (which has been observed in obese animal models) and thereby to improve glucose and lipid metabolism, regulate food intake and energy balance, and to produce clinically meaningful weight loss. − However, in 2008 rimonabant was withdrawn from the market due to its association with serious drug related psychiatric adverse events, which included depressed mood disorders and anxiety . Except for the observed psychiatric adverse events, rimonabant had displayed a favorable safety profile during the time it had been on the market.…”

Section: Introductionmentioning

confidence: 99%

Bioactivation of the Cannabinoid Receptor Antagonist Rimonabant to a Cytotoxic Iminium Ion Metabolite

Foster

Prime²,

Gustafsson³

et al. 2012

Chem. Res. Toxicol.

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The cannabinoid type 1 receptor (CB1r) antagonist rimonabant was approved in 2006 for the treatment of obesity but was withdrawn in 2008 due to serious drug-related psychiatric disorders. In vitro metabolism studies with rimonabant have revealed high levels of reactive metabolite formation, which resulted in irreversible time-dependent P450 3A4 inhibition and in covalent binding to microsomal proteins. In the present study, an in vitro approach has been used to explore whether metabolic bioactivation of rimonabant might result in cell toxicity. A panel of SV40-T-antigen-immortalized human liver derived (THLE) cells that had been transfected with vectors encoding various human cytochrome P450 enzymes (THLE-1A2, 2C9, 2C19, 2D6, and 3A4) or with an empty vector (THLE-Null) were exposed to rimonabant. Cell toxicity and covalent binding to cellular proteins were evaluated, as was metabolite formation. Rimonabant exhibited markedly potentiated dose and time dependent cytotoxicity to THLE-3A4 cells, compared to that of all other THLE cell lines. This was accompanied by high levels of covalent binding of [(14)C]-rimonabant to THLE-3A4 cell proteins (1433 pmol drug equivalents/mg protein) and the formation of several metabolites that were not generated by THLE-Null cells. These included N-aminopiperidine (NAP) and an iminium ion species. However, no toxicity was observed when THLE cells were incubated with NAP. Glutathione depletion did not alter the observed potent cell cytotoxicity of rimonabant to THLE-3A4 cells. Preincubation of THLE-3A4 cells with the cytochrome P450 3A4 inhibitor ritonavir blocked the selective toxicity of rimonabant to these cells. In addition, ritonavir pretreatment blocked the metabolism of the compound in the cells and thereby significantly decreased the covalent binding of [(14)C]-rimonabant to THLE-3A4 cell proteins. We conclude that the potent toxicity of rimonabant in THLE-3A4 cells occurs by a mechanistic sequence, which is initiated by cytochrome P450 3A4 mediated formation of a highly cytotoxic reactive iminium ion metabolite that binds covalently to cellular proteins.

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Thromboangiitis Obliterans

Akar¹,

Durdu²

2010

Rutherford's Vascular Surgery

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Update on Rimonabant—A Selective Cannabinoid CB1 Antagonist

Cited by 5 publications

References 3 publications

Use of Electrochemical Oxidation and Model Peptides To Study Nucleophilic Biological Targets of Reactive Metabolites: The Case of Rimonabant

Use of Electrochemical Oxidation and Model Peptides To Study Nucleophilic Biological Targets of Reactive Metabolites: The Case of Rimonabant

Bioactivation of the Cannabinoid Receptor Antagonist Rimonabant to a Cytotoxic Iminium Ion Metabolite

Thromboangiitis Obliterans

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