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Novel highly potent OXE receptor antagonists with prolonged plasma lifetimes that are converted to active metabolites in vivo in monkeys.

Author(s): Ye Q, Chourey S, Reddy CN, Wang R, Cossette C, Gravel S, Slobodchikova I, Vuckovic D, Rokach J, Powell WS

Br J Pharmacol. 2019 Oct 26;: Authors: Ye Q, Chourey S, Reddy CN, Wang R, Cossette C, Gravel S, Slobodchikova I, Vuckovic D, Rokach J, Powell WS

Article GUID: 31655025
Pharmacokinetics and Metabolism of Selective Oxoeicosanoid (OXE) Receptor Antagonists and Their Effects on 5-Oxo-6,8,11,14-eicosatetraenoic Acid (5-Oxo-ETE)-Induced Granulocyte Activation in Monkeys.

Author(s): Cossette C, Chourey S, Ye Q, Nagendra Reddy C, Gore V, Gravel S, Slobodchikova I, Vuckovic D, Rokach J, Powell WS

J Med Chem. 2016 11 23;59(22):10127-10146 Authors: Cossette C, Chourey S, Ye Q, Nagendra Reddy C, Gore V, Gravel S, Slobodchikova I, Vuckovic D, Rokach J, Powell WS

Article GUID: 27766872
In vivo α-hydroxylation of a 2-alkylindole antagonist of the OXE receptor for the eosinophil chemoattractant 5-oxo-6,8,11,14-eicosatetraenoic acid in monkeys.

Author(s): Chourey S, Ye Q, Reddy CN, Cossette C, Gravel S, Zeller M, Slobodchikova I, Vuckovic D, Rokach J, Powell WS

Biochem Pharmacol. 2017 08 15;138:107-118 Authors: Chourey S, Ye Q, Reddy CN, Cossette C, Gravel S, Zeller M, Slobodchikova I, Vuckovic D, Rokach J, Powell WS

Article GUID: 28476332
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.

Author(s): Reddy CN, Alhamza H, Chourey S, Ye Q, Gore V, Cossette C, Gravel S, Slobodchikova I, Vuckovic D, Rokach J, Powell WS

Eur J Pharm Sci. 2018 Mar 30;115:88-99 Authors: Reddy CN, Alhamza H, Chourey S, Ye Q, Gore V, Cossette C, Gravel S, Slobodchikova I, Vuckovic D, Rokach J, Powell WS

Article GUID: 29339225
Corrigendum to "In vivo α-hydroxylation of a 2-alkylindole antagonist of the OXE receptor for the eosinophil chemoattractant 5-oxo-6,8,11,14-eicosatetraenoic acid in monkeys" [Biochem. Pharmacol. 138 (2017) 107-118].

Author(s): Chourey S, Ye Q, Reddy CN, Cossette C, Gravel S, Zeller M, Slobodchikova I, Vuckovic D, Rokach J, Powell WS

Biochem Pharmacol. 2018 08;154:174 Authors: Chourey S, Ye Q, Reddy CN, Cossette C, Gravel S, Zeller M, Slobodchikova I, Vuckovic D, Rokach J, Powell WS PMID: 29754018 [PubMed]

Article GUID: 29754018
Novel Highly Potent and Metabolically Resistant Oxoeicosanoid (OXE) Receptor Antagonists That Block the Actions of the Granulocyte Chemoattractant 5-Oxo-6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE).

Author(s): Chourey S, Ye Q, Reddy CN, Wang R, Cossette C, Gravel S, Slobodchikova I, Vuckovic D, Rokach J, Powell WS

J Med Chem. 2018 Jul 26;61(14):5934-5948 Authors: Chourey S, Ye Q, Reddy CN, Wang R, Cossette C, Gravel S, Slobodchikova I, Vuckovic D, Rokach J, Powell WS

Article GUID: 29972644
Title:Novel highly potent OXE receptor antagonists with prolonged plasma lifetimes that are converted to active metabolites in vivo in monkeys.
Authors:Ye Q,  Chourey S,  Reddy CN,  Wang R,  Cossette C,  Gravel S,  Slobodchikova I,  Vuckovic D,  Rokach J,  Powell WS
Link:https://www.ncbi.nlm.nih.gov/pubmed/31655025?dopt=Abstract
DOI:10.1111/bph.14874
Category:Br J Pharmacol
PMID:31655025
Dept Affiliation: PERFORM
1 Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, Melbourne, Florida.
2 Meakins-Christie Laboratories, Centre for Translational Biology, McGill University Health Centre, Montreal, QC, Canada.
3 Department of Chemistry and Biochemistry and PERFORM Centre, Concordia University, Montreal, QC, Canada.

Description:

Novel highly potent OXE receptor antagonists with prolonged plasma lifetimes that are converted to active metabolites in vivo in monkeys.

Br J Pharmacol. 2019 Oct 26;:

Authors: Ye Q, Chourey S, Reddy CN, Wang R, Cossette C, Gravel S, Slobodchikova I, Vuckovic D, Rokach J, Powell WS

Abstract

BACKGROUND AND PURPOSE: The 5-lipoxygenase product 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), acting through the OXE receptor, is a potent eosinophil chemoattractant that may be an important proinflammatory mediator in eosinophilic diseases such as asthma. We previously identified a series of indole-based OXE receptor antagonists that rapidly appear in the blood following oral administration but have limited lifetimes. The objective of this study was to increase the potency and plasma half-lives of these compounds and thereby identify the optimal candidate for future preclinical studies in monkeys, since rodents do not have an OXE receptor ortholog.

EXPERIMENTAL APPROACH: We synthesized a series of substituted phenylalkyl indoles and compared their antagonist potencies, pharmacokinetics, and metabolism to those of our earlier compounds. The potencies of some of their metabolites were also investigated.

KEY RESULTS: Among the compounds tested, the S-enantiomer of the m-chlorophenyl compound (S-Y048) was the most potent, with an pIC50 of about 10.8 for inhibition of 5-oxo-ETE-induced calcium mobilization in human neutrophils. When administered orally to cynomolgus monkeys, S-Y048 rapidly appeared in the blood and had a half-life in plasma of over 7 h, considerably longer than any of the other OXE analogs tested. A major hydroxylated metabolite, with a potency close to that of its precursor, was identified in plasma.

CONCLUSION AND IMPLICATIONS: Because of its highly potent antagonist activity and its long lifetime in vivo, S-Y048 may be a useful anti-inflammatory agent for the treatment of eosinophilic diseases such as asthma, allergic rhinitis, and atopic dermatitis.

PMID: 31655025 [PubMed - as supplied by publisher]