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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
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]