In Vitro Metabolism of Diarylpyrazoles, a Novel Group of Cannabinoid Receptor Ligands

Zhang, Qiang; Ma, Peng; Wang, Weiqun; Cole, Richard B.; Wang, Guangdi

doi:10.1124/dmd.104.001974

Cited by 12 publications

(15 citation statements)

References 14 publications

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“…The metabolism of rimonabant in RLM incubations has been reported previously (Zhang et al, 2005a). In the present study, masses of metabolites detected were consistent with the literature report.…”

Section: Discussionsupporting

confidence: 82%

“…This shows that CA2, but not M3, forms the iminium ion (M7) upon collision-induced fragmentation. Zhang et al (2005a) proposed that the major rimonabant metabolites, denoted M3 and M7 in the present study, are the 2-hydroxypiperidinyl metabolite (an ␣-carbinolamine) and the 2,3-or 3,4-dehydropiperidinyl species. These conclusions are not supported by our results.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the identification of M7 as a reactive iminium ion (the 1,2-dehydropiperidinyl species) is supported by the depletion of M7 by cyanide and the formation of large amounts of the corresponding cyano adduct CA2. However, it should be noted that the 2,3-dehydropiperidinyl species suggested by Zhang et al (2005a) is the conjugate base of the iminium ion.…”

Section: Discussionmentioning

confidence: 99%

“…We propose that M3 is the 3-hydroxypiperidinyl metabolite and M7 the 1,2-dehydropiperidinyl species. Zhang et al (2005a) suggested that M3 is an ␣-carbinolamine. This system is generally unstable and undergoes cleavage to give the corresponding amine and aldehyde (or in the case of cyclic ␣-carbinolamines, to give the corresponding aminoaldehyde as shown in Scheme 1) that may be metabolized further to the carboxylic acid and/or alcohol as stable end products.…”

Section: Discussionmentioning

confidence: 99%

“…Three major metabolites were detected in both HLMs and RLMs, N-aminopiperidine M1, the monooxygenated metabolite M3 (ϩ16 Da), and the dehydrogenated metabolite M7 (Ϫ2 Da) (Scheme 2). M1 was not reported by Zhang et al (2005a) but is a known metabolite of rimonabant (EMEA, 2006, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_ Scientific_Discussion/human/000666/WC500021284.pdf). Minor metabolites detected were M6 (ϩ16 Da, RLMs and HLMs) and M2, M4, M5, and M8 (all ϩ14 Da, HLMs only) (Scheme 2).…”

Section: Discussionmentioning

confidence: 99%

See 4 more Smart Citations

Bioactivation Pathways of the Cannabinoid Receptor 1 Antagonist Rimonabant

Bergström¹,

Isin²,

Castagnoli³

et al. 2011

Drug Metab Dispos

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ABSTRACT:In the present work, the characterization of the biotransformation and bioactivation pathways of the cannabinoid receptor 1 antagonist rimonabant (Acomplia) is described. Rimonabant was approved in Europe in 2006 for the treatment of obesity but was withdrawn in 2008 because of a significant drug-related risk of serious psychiatric disorders. The aim of the present work is to characterize the biotransformation and potential bioactivation pathways of rimonabant in vitro in human and rat liver microsomes. The observation of a major iminium ion metabolite led us to perform reactive metabolite trapping, covalent binding to proteins, and time-dependent inhibition of cytochrome P450 3A4 studies. The major biotransformation pathways were oxidative dehydrogenation of the piperidinyl ring to an iminium ion, hydroxylation of the 3 position of the piperidinyl ring, and cleavage of the amide linkage. In coincubations with potassium cyanide, three cyanide adducts were detected. A high level of covalent binding of rimonabant in human liver microsomes was observed (920 pmol equivalents/mg protein). In coincubations with potassium cyanide and methoxylamine, the covalent binding was reduced by approximately 40 and 30%, respectively, whereas GSH had no significant effect on covalent binding levels. Rimonabant was also found to inhibit cytochrome P450 3A4 irreversibly in a time-dependent manner. In view of these findings, it is noteworthy that, to date, no toxicity findings related to the formation of reactive metabolites from rimonabant have been reported.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Bioactivation Pathways of the Cannabinoid Receptor 1 Antagonist Rimonabant

Bergström¹,

Isin²,

Castagnoli³

et al. 2011

Drug Metab Dispos

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Synthesis of Newly Substituted Pyrazoles and Substituted Pyrazolo[3,4‐b]Pyridines Based on 5‐Amino‐3‐Methyl‐1‐Phenylpyrazole

El‐Emary

2007

J Chinese Chemical Soc

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The reaction of the aminopyrazole 1 with benzenesulfonyl chloride, arenediazonium salt, chloroacetyl chloride, ethoxy methyleneamlononitrile and with ethyl 2‐cyano‐3‐ethoxyacrylate gave the substituted 3‐methyl‐1‐phenylpyrazole 2–5a,b. Compound 5b was cyclized to 6 and to 7 by treating it with AlCl3 and with POCl3, respectively. Compound 6 converted to 7 by boiling it in POCl3/PCl5. Compound 10b was produced through reaction of 9 with acetophenone. Reaction of 1 with benzylidinemalononitrile afforded 11. New methods for preparation of 15 and 16 are described. The reaction of 8 with malononitrile, thiosemicarbazide, phenyl hydrazine and acetophenone afforded compounds 18–21. The reaction of 21 with malononitrile gave 22. Compounds 23–26 were produced upon reaction of 10a with malononitrile, phenyl hydrazine, thiosemicarbazide, semicarbazide and with benzaldehyde, respectively.

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Identification of in vitro metabolites of JWH-015, an aminoalkylindole agonist for the peripheral cannabinoid receptor (CB2) by HPLC-MS/MS

Zhang

Cole

et al. 2006

Anal Bioanal Chem

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The in vitro microsomal metabolism of JWH-015, a ligand that exhibits a high binding affinity at the peripheral cannabinoid receptor CB(2), has been studied. A total of 22 metabolites were identified and structurally characterized. The metabolites are products of: 1) monohydroxylation on the naphthalene ring (m/z 344, M20 and M21), indole ring (m/z 344, M17 and M18), or the N-alkyl group (m/z 344, M14); 2) arene oxidation leading to dihydrodiols (m/z 362, M12 and M15); 3) dihydroxylation on the naphthalene ring (m/z 360, M7) or indole ring (m/z 360, M13), resulting from a combination of monohydroxylations on both the naphthalene and indole rings (m/z 360, M16), or a combination of monohydroxylations on the naphthalene ring and on the N-propyl group (m/z 360, M9); 4) trihydroxylation (m/z 378, M1, M3, M4, M6, and M10); 5) N-dealkylation (m/z 286, M19); 6) N-dealkylation and monohydroxylation on the naphthalene ring (m/z 302, M11); 7) N-dealkylation and dihydrodiol formation from arene oxidation (m/z 320, M2 and M5); 8) dehydrogenation after monohydroxylation on the N-alkyl group (m/z 326, M22); 9) dehydrogenation and monohydroxylation on the indole ring (m/z 342, M8).

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In Vitro Metabolism of Diarylpyrazoles, a Novel Group of Cannabinoid Receptor Ligands

Cited by 12 publications

References 14 publications

Bioactivation Pathways of the Cannabinoid Receptor 1 Antagonist Rimonabant

Bioactivation Pathways of the Cannabinoid Receptor 1 Antagonist Rimonabant

Synthesis of Newly Substituted Pyrazoles and Substituted Pyrazolo[3,4‐b]Pyridines Based on 5‐Amino‐3‐Methyl‐1‐Phenylpyrazole

Identification of in vitro metabolites of JWH-015, an aminoalkylindole agonist for the peripheral cannabinoid receptor (CB2) by HPLC-MS/MS

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