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Research ArticleArticle

CYP2C8- and CYP3A-Mediated C-Demethylation of (3-{[(4-tert-Butylbenzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic Acid (CP-533,536), an EP2 Receptor-Selective Prostaglandin E2 Agonist: Characterization of Metabolites by High-Resolution Liquid Chromatography-Tandem Mass Spectrometry and Liquid Chromatography/Mass Spectrometry-Nuclear Magnetic Resonance

Chandra Prakash, Weiwei Wang, Thomas O'Connell and Kim A. Johnson
Drug Metabolism and Disposition October 2008, 36 (10) 2093-2103; DOI: https://doi.org/10.1124/dmd.108.022897
Chandra Prakash
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Weiwei Wang
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Thomas O'Connell
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Kim A. Johnson
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Abstract

CP-533,536, (3-{[(4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic acid (1), an EP2 receptor-selective prostaglandin E2 agonist, is being developed to aid in the healing of bone fractures. To support the development of this program, in vitro metabolism of 1 was investigated in human liver microsomes and major recombinant human cytochrome P450 (P450) isoforms. 1 was metabolized in vitro by at least three recombinant human P450s: CYP3A4, CYP3A5, and CYP2C8. The turnover of 1 was NADPH-dependent and was completely inhibited by ketoconazole and quercetin in the CYP3A4/5 and CYP2C8 incubations, respectively. The major metabolic pathways were caused by oxidation of the tert-butyl moiety to form the ω-hydroxy metabolite (M4), oxidation of the pyridine moiety, and/or N-dealkylation of the methylphenoxy acetic acid moiety. The alcohol metabolite M4 was further oxidized to the corresponding carboxylic acid M3. In addition to these pathways, three unusual metabolites (M22, M23, and M26) resulting from C-demethylation of the tert-butyl group were identified using high-resolution liquid chromatography/tandem mass spectrometry and liquid chromatography/mass spectrometry/NMR. The C-demethylated metabolites were not detected on incubation of carboxylic acid metabolite M3 with either human liver microsomes or CYP3A/2C8 isoforms, suggesting that these metabolites were not derived from decarboxylation of M3. A possible mechanism for C-demethylation may involve the oxidation of M4 to form an aldehyde metabolite (M24), followed by P450-mediated deformylation, to give an unstable carbon-centered radical and formic acid. The carbon-centered radical intermediate then undergoes either oxygen rebound to form an alcohol metabolite M23 or hydrogen abstraction leading to an olefin metabolite M26.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.022897.

  • ABBREVIATIONS: PGE2, prostaglandin E2; 1, CP-533,536, (3-{[(4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino]methyl}-phenoxy)-acetic acid; P450, cytochrome P450; LC/MS/MS, liquid chromatography/tandem mass spectrometry; NMR, nuclear magnetic resonance; HLM, human liver microsome; HPLC, high-performance liquid chromatography; M3, 2-(4-{[(3-carboxymethoxy-benzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenyl)-2-methyl-propionic acid; M4, (3-{[[4-(2-hydroxy-1,1-dimethyl-ethyl)-benzyl]-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic acid; CID, collision-induced dissociation; LC15-0133, 1-[2-(5-tert-butyl-[1,3,4]oxadiazole-2-carbonyl)-4-fluoro-pyrrolidin-1-yl]-2-(2-hydroxy-1,1-dimethylethylamino)ethanone.

  • ↵1 Current affiliation: Drug Metabolism and Pharmacokinetics, Biogen Idec, Cambridge, MA.

    • Received June 13, 2008.
    • Accepted July 22, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (10)
Drug Metabolism and Disposition
Vol. 36, Issue 10
1 Oct 2008
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Research ArticleArticle

CYP2C8- and CYP3A-Mediated C-Demethylation of (3-{[(4-tert-Butylbenzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic Acid (CP-533,536), an EP2 Receptor-Selective Prostaglandin E2 Agonist: Characterization of Metabolites by High-Resolution Liquid Chromatography-Tandem Mass Spectrometry and Liquid Chromatography/Mass Spectrometry-Nuclear Magnetic Resonance

Chandra Prakash, Weiwei Wang, Thomas O'Connell and Kim A. Johnson
Drug Metabolism and Disposition October 1, 2008, 36 (10) 2093-2103; DOI: https://doi.org/10.1124/dmd.108.022897

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Research ArticleArticle

CYP2C8- and CYP3A-Mediated C-Demethylation of (3-{[(4-tert-Butylbenzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic Acid (CP-533,536), an EP2 Receptor-Selective Prostaglandin E2 Agonist: Characterization of Metabolites by High-Resolution Liquid Chromatography-Tandem Mass Spectrometry and Liquid Chromatography/Mass Spectrometry-Nuclear Magnetic Resonance

Chandra Prakash, Weiwei Wang, Thomas O'Connell and Kim A. Johnson
Drug Metabolism and Disposition October 1, 2008, 36 (10) 2093-2103; DOI: https://doi.org/10.1124/dmd.108.022897
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