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.

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.

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.

The potent eosinophil chemoattractant 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a 5-lipoxygenase product that acts via the selective OXE receptor, which is present in many species, but not rodents. We previously reported that the indole 230 is a potent human OXE receptor antagonist. The objective of the present study was to determine whether the monkey would be a suitable animal model to investigate its pharmaceutical potential.

Biosynthesis and actions of 5-oxoeicosatetraenoic acid (5-oxo-ETE) on feline granulocytes.

The 5-lipoxygenase product 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is the most powerful human eosinophil chemoattractant among lipid mediators and could play a major pathophysiological role in eosinophilic diseases such as asthma. Its actions are mediated by the OXE receptor, orthologs of which are found in many species from humans to fish, but not rodents. The unavailability of rodent models to examine the pathophysiological roles of 5-oxo-ETE and the OXE receptor has substantially hampered progress in this area.

Two Potent OXE-R Antagonists: Assignment of Stereochemistry.

5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is formed by the oxidation of 5-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-HETE), which is a major metabolite of enzymatic oxidation of arachidonic acid (AA). 5-Oxo-ETE is the most potent lipid chemoattractant for human eosinophils. Its actions are mediated by the selective OXE receptor, which is therefore an attractive target in eosinophilic diseases such as allergic rhinitis and asthma.

Base-dependent formation of cis and trans olefins and their application in the synthesis of 5-oxo-ETE receptor antagonists.

5-Oxo-ETE is the most potent eosinophil chemoattractant among lipid mediators. We have developed two 5-oxo-ETE receptor antagonists. In the course of the work, we have developed a procedure to selectively introduce a cis and trans double bond in an alkyl side chain.

Inhibition of 5-oxo-6,8,11,14-eicosatetraenoic acid-induced activation of neutrophils and eosinophils by novel indole OXE receptor antagonists.

5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a 5-lipoxygenase product that is a potent granulocyte chemoattractant, which induces the infiltration of eosinophils into human skin when injected intradermally. It could therefore be an important proinflammatory mediator in eosinophilic diseases such as asthma and allergic rhinitis, and the OXE receptor, which mediates its actions, is therefore an attractive drug target. Using a structure-based approach in which substituents mimicking the essential polar (C1-C5) and hydrophobic (C15-C20) regions of 5-oxo-ETE were incorporated on an indole scaffold, we identified two potent selective OXE antagonists with IC50 values of about 30 nM.

5-Oxo-ETE receptor antagonists.

5-Oxo-ETE is the most powerful eosinophil chemoattractant among lipid mediators. Eosinophil infiltration into the lungs of asthmatics may be responsible for the late phase of inflammatory asthma. We have designed and synthesized a 5-oxo-ETE receptor antagonist, the purpose of which is to prevent eosinophil migration to the lung during an asthma attack and thereby reduce asthma symptoms.

C20-trifluoro-5-oxo-ETE: a metabolically stable 5-oxo-ETE derivative.

The total synthesis of C(20)-trifluoro-6(E),8(Z),11(Z),14(Z) 5-oxo-ETE is reported. This compound was designed as an ω-oxidation-resistant analog of 5-oxo-ETE that would be resistant to metabolism. The trifluoro derivative of 5-oxo-ETE stimulated calcium mobilization in neutrophils and desensitized these cells to subsequent exposure to 5-oxo-ETE.

A new approach to the synthesis of polyunsaturated deuterated isoprostanes: total synthesis of d4-5-epi-8,12-iso-iPF3alpha-VI and d4-8,12-iso-iPF3alpha-VI.

The total and stereospecific synthesis of d(4)-5-epi-8,12-iso-iPF(3alpha)-VI 55 and d(4)-8,12-iso-iPF(3alpha)-VI 64, EPA-derived all-syn-isoprostanes (iPs), has been accomplished. Because of issues related to volatility and yield with some of the primary deuterated synthons an improved synthesis is presented. These two deuterated analogs were used to discover and quantify the presence of the corresponding endogenous isoprostanes in human urine.