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Metabolism and pharmacokinetics of a potent N -acylindole antagonist of the OXE receptor for the eosinophil chemoattractant 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) in rats and monkeys

Title:

Metabolism and pharmacokinetics of a potent N -acylindole antagonist of the OXE receptor for the eosinophil chemoattractant 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) in rats and monkeys

Reddy, Chintam Nagendra, Alhamza, Hussam, Chourey, Shishir, Ye, Qiuji, Gore, Vivek, Cossette, Chantal, Gravel, Sylvie, Slobodchikova, Irina, Vuckovic, Dajana, Rokach, Joshua and Powell, William S. (2018) Metabolism and pharmacokinetics of a potent N -acylindole antagonist of the OXE receptor for the eosinophil chemoattractant 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) in rats and monkeys. European Journal of Pharmaceutical Sciences . pp. 1-59. ISSN 09280987 (In Press)

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Official URL: http://dx.doi.org/10.1016/j.ejps.2018.01.021

Abstract

We previously identified the indole 264 as a potent in vitro antagonist of the human OXE receptor that mediates the actions of the powerful eosinophil chemoattractant 5-oxo-ETE. No antagonists of this receptor are currently commercially available or are being tested in clinical studies. The lack of a rodent ortholog of the OXE receptor has hampered progress in this area because of the unavailability of commonly used mouse or rat animal models. In the present study, we examined the feasibility of using the cynomolgus monkey as an animal model to investigate the efficacy of orally administered 264 in future in vivo studies. We first confirmed that 264 is active in monkeys by showing that it is a potent inhibitor of 5-oxo-ETE-induced actin polymerization and chemotaxis in granulocytes. The major microsomal metabolites of 264 were identified by cochromatography with authentic chemically synthesized standards and LC-MS/MS as its ω2-hydroxy and ω2-oxo derivatives, formed by ω2-oxidation of its hexyl side chain. Small amounts of ω1-oxidation products were also identified. None of these metabolites have substantial antagonist potency. High levels of 264 appeared rapidly in the blood following oral administration to both rats and monkeys, and declined to low levels by 24 h. As with microsomes, its major plasma metabolites in monkeys were ω2-oxidation products. We conclude that the monkey is a suitable animal model to investigate potential therapeutic effects of 264. This, or a related compound with diminished susceptibility to ω2-oxidation, could be a useful therapeutic agent in eosinophilic disorders such as asthma.

Divisions:Concordia University > Faculty of Arts and Science > Chemistry and Biochemistry
Item Type:Article
Refereed:Yes
Authors:Reddy, Chintam Nagendra and Alhamza, Hussam and Chourey, Shishir and Ye, Qiuji and Gore, Vivek and Cossette, Chantal and Gravel, Sylvie and Slobodchikova, Irina and Vuckovic, Dajana and Rokach, Joshua and Powell, William S.
Journal or Publication:European Journal of Pharmaceutical Sciences
Date:12 January 2018
Funders:
  • Canadian Institutes of Health Research [Grants MOP-6254 and PP2-133388 (WSP)]
  • American Asthma Foundation [Grant 12-0049 (JR)]
  • National Heart, Lung, and Blood Institute [Grant R01HL081873 (JR)]
  • Le Fond de la Recherche en Santé du Québec
  • J. T. Costello Memorial Research Fund
  • Natural Sciences and Engineering Research Council of Canada [Grant RGPIN/435814-2103]
Digital Object Identifier (DOI):10.1016/j.ejps.2018.01.021
Keywords:5-Oxo-ETE; OXE receptor antagonist; Eicosanoids; 5-Lipoxygenase products; Eosinophils; Drug metabolism
ID Code:983414
Deposited By: DANIELLE DENNIE
Deposited On:19 Jan 2018 14:21
Last Modified:10 Apr 2019 00:00

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