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Metabolism of anti-inflammatory OXE (oxoeicosanoid) receptor antagonists by nonhuman primates

Authors: Cossette CChourey SYe QReddy CNWang RPoulet SSlobodchikova IVuckovic DRokach JPowell WS


Affiliations

1 Meakins-Christie Laboratories, Centre for Translational Biology, McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC H4A 3J1, Canada.
2 Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, 150 West University Boulevard, Melbourne, FL 32901-6982, USA.
3 Department of Chemistry and Biochemistry and PERFORM Centre, Concordia University, 7141 Sherbrooke St. W., Montréal, QC H4B 1R6, Canada.
4 Meakins-Christie Laboratories, Centre for Translational Biology, McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC H4A 3J1, Canada. Electronic address: william.powell@mcgill.ca.

Description

5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is the only product of the proinflammatory 5-lipoxygenase pathway with potent chemoattractant effects for human eosinophils, suggesting an important role in eosinophilic diseases such as asthma. 5-Oxo-ETE, acting through its selective OXE receptor, induces dermal eosinophilia in both humans and monkeys. To block its effects, we designed selective indole-based OXE antagonists containing hexyl (S-230) or phenylhexyl (S-C025 and S-Y048) side chains, which inhibit allergen-induced dermal and pulmonary inflammation in monkeys, suggesting that they may be useful therapeutic agents in humans. In this study we identified two metabolic pathways for the phenylhexyl-containing antagonists in liver microsomes: benzylic and N-methyl hydroxylation, resulting in ?-hydroxy, ?-oxo, and NH-containing products with reduced potencies that were identified by mass spectrometry and comparison with synthetic standards. Products of both pathways were also identified in monkey plasma following oral administration of S-C025 and S-Y025, but were less abundant than the a-hydroxy metabolites that we previously identified. Interestingly, the a-hydroxy compounds were not detected in microsomal incubations, suggesting a different origin. The relative rates of metabolism of these antagonists were S-230 >> S-C025 > S-Y048, which may help to explain the differences in their plasma half-lives (S-230 < S-C025 < S-Y048). In conclusion, S-C025 and S-Y048 are metabolized by liver microsomes by benzylic and N-methyl hydroxylation but not by a-hydroxylation, whereas all three pathways exist in vivo. Addition of a phenyl group to the hexyl side chain of these antagonists dramatically reduced their rates of metabolism, which would explain their prolonged in vivo half-lives.


Keywords: 5-Lipoxygenase products5-oxo-ETEEicosanoidsInflammationN-demethylationbenzylic hydroxylation


Links

PubMed: https://pubmed.ncbi.nlm.nih.gov/35158054/

DOI: 10.1016/j.ejps.2022.106144