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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 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).
Authors:Chourey S,  Ye Q,  Reddy CN,  Wang R,  Cossette C,  Gravel S,  Slobodchikova I,  Vuckovic D,  Rokach J,  Powell WS
Link:https://www.ncbi.nlm.nih.gov/pubmed/29972644?dopt=Abstract
DOI:10.1021/acs.jmedchem.8b00154
Category:J Med Chem
PMID:29972644
Dept Affiliation: PERFORM
1 Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology , 150 West University Boulevard , Melbourne , Florida 32901-6982 , United States.
2 Meakins-Christie Laboratories, Centre for Translational Biology , McGill University Health Centre , 1001 Decarie Boulevard , Montreal , Quebec H4A 3J1 , Canada.
3 Department of Chemistry and Biochemistry and PERFORM Centre , Concordia University , 7141 Sherbrooke Street West , Montréal , Quebec H4B 1R6 , Canada.

Description:

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).

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

Abstract

5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a potent lipid mediator that induces tissue eosinophilia via the selective OXE receptor (OXE-R), which is an attractive therapeutic target in eosinophilic diseases. We previously identified indole OXE-R antagonists that block 5-oxo-ETE-induced primate eosinophil activation. Although these compounds possess good oral absorption, their plasma levels decline rapidly due to extensive oxidation of their hexyl side chain. We have now succeeded in dramatically increasing antagonist potency and resistance to metabolism by replacing the hexyl group with phenylpentyl or phenylhexyl side chains. Compared with our previous lead compound S-230, our most potent antagonist, S-C025, has an IC50 (120 pM) over 80 times lower and a substantially longer plasma half-life. A single major metabolite, which retains antagonist activity (IC50, 690 pM) and has a prolonged lifetime in plasma was observed. These new highly potent OXE-R antagonists may provide a novel strategy for the treatment of eosinophilic disorders like asthma.

PMID: 29972644 [PubMed - in process]