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; Powell, William S.

doi:10.1016/j.ejps.2018.01.021

Cited by 7 publications

(15 citation statements)

References 29 publications

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“…We next focused on the cynomolgus monkey, which was available to us locally. Our initial feasibility studies showed that both 230 (Cossette et al, ) and 264 (Reddy et al, ) are potent in vitro OXE receptor antagonists in this species and appear rapidly in the blood following oral administration. This led us to investigate whether they could inhibit eosinophil infiltration following in vivo administration to these animals.…”

Section: Discussionmentioning

confidence: 99%

“…Three days later, all food was withdrawn at the end of the afternoon. The following morning, the appropriate amounts of racemic 230 (Gore et al, ) or racemic 264 (Reddy et al, ), synthesized as described previously, were dissolved in ethanol and diluted with 10 volumes of 20‐mM NaHCO 3 , pH 8.0. After vortexing, either vehicle alone, or the resulting antagonist suspensions (4.4 ml·kg −1 ) were administered by oral gavage at doses of either 30 mg·kg −1 ( 230 ) or 75 mg·kg −1 ( 264 ).…”

Section: Methodsmentioning

confidence: 99%

“…For the experiments with Ascaris , two additional identical doses of antagonist were administered after 8 and 16 hr. The plasma levels of 230 (Cossette et al, ) and 264 (Reddy et al, ) in blood samples (1 ml), collected 24 hr after injection of Ascaris , were measured by reversed‐phase HPLC as described previously.…”

Section: Methodsmentioning

confidence: 99%

“…FIGURE 1 Formation of 5-oxo-ETE and inhibition of its actions by OXE receptor antagonists two compounds, 230 and 264 ( Figure 1), with in vitro potencies of about 30 nM and oral bioavailability in monkeys (Cossette et al, 2016;Reddy et al, 2018). Both compounds contain a chiral carbon due to the presence of a methyl group in the 3-position of the carboxyl side chain, with the S-enantiomers accounting for nearly all of the antagonist activity Patel et al, 2014).…”

Section: What Is the Clinical Significancementioning

confidence: 99%

“…We recently initiated a program to identify synthetic OXE receptor antagonists by creating conformationally restricted compounds using an indole scaffold to which were attached regions of the 5‐oxo‐ETE molecule that are essential for activation of its receptor. We identified two compounds, 230 and 264 (Figure ), with in vitro potencies of about 30 nM (Gore et al, ) and oral bioavailability in monkeys (Cossette et al, ; Reddy et al, ). Both compounds contain a chiral carbon due to the presence of a methyl group in the 3‐position of the carboxyl side chain, with the S ‐enantiomers accounting for nearly all of the antagonist activity (Gore et al, ; Patel et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of allergen‐induced dermal eosinophilia by an oxoeicosanoid receptor antagonist in non‐human primates

Miller

Cossette

Chourey

et al. 2020

British J Pharmacology

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Background and Purpose: 5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), acting via the OXE receptor, is unique among 5-lipoxygenase products in its ability to directly induce human eosinophil migration, suggesting its involvement in eosinophilic diseases. To address this hypothesis, we synthesized selective indole-based OXE receptor antagonists. Because rodents lack an OXE receptor orthologue, we sought to determine whether these antagonists could attenuate allergen-induced skin eosinophilia in sensitized monkeys.Experimental Approach: In a pilot study, cynomolgus monkeys with environmentally acquired sensitivity to Ascaris suum were treated orally with the "firstgeneration" OXE antagonist 230 prior to intradermal injection of 5-oxo-ETE or Ascaris extract. Eosinophils were evaluated in punch biopsy samples taken 6 or 24 hr later.We subsequently treated captive-bred rhesus monkeys sensitized to house dust mite (HDM) allergen with a more recently developed OXE antagonist, S-Y048, and evaluated its effects on dermal eosinophilia induced by either 5-oxo-ETE or HDM.Key Results: In a pilot experiment, both 5-oxo-ETE and Ascaris extract induced dermal eosinophilia in cynomolgus monkeys, which appeared to be reduced by 230. Subsequently, we found that the related OXE antagonist S-Y048 is a highly potent inhibitor of 5-oxo-ETE-induced activation of rhesus monkey eosinophils in vitro and has a half-life in plasma of about 6 hr after oral administration. S-Y048 significantly inhibited eosinophil infiltration into the skin in response to both intradermally administered 5-oxo-ETE and HDM.Conclusions and Implications: 5-Oxo-ETE may play an important role in allergeninduced eosinophilia. Blocking its effects with S-Y048 may provide a novel therapeutic approach for eosinophilic diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: What Is the Clinical Significancementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of allergen‐induced dermal eosinophilia by an oxoeicosanoid receptor antagonist in non‐human primates

Miller

Cossette

Chourey

et al. 2020

British J Pharmacology

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Targeting the OXE receptor as a potential novel therapy for asthma

Powell

Rokach

2020

Biochemical Pharmacology

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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)

Chourey

Reddy

et al. 2018

J. Med. Chem.

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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 IC (120 pM) over 80 times lower and a substantially longer plasma half-life. A single major metabolite, which retains antagonist activity (IC, 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.

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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

Cited by 7 publications

References 29 publications

Inhibition of allergen‐induced dermal eosinophilia by an oxoeicosanoid receptor antagonist in non‐human primates

Inhibition of allergen‐induced dermal eosinophilia by an oxoeicosanoid receptor antagonist in non‐human primates

Targeting the OXE receptor as a potential novel therapy for asthma

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)

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