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

Abstract

Background and Purpose: The 5-lipoxygenase product 5-oxo-6E,8Z,11Z,14Zeicosatetraenoic 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 indolebased 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, as rodents do not have an OXE receptor orthologue.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 mchlorophenyl compound (S-Y048) was the most potent, with an pIC 50 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 hr, considerably longer than any of the other OXE analogues 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.

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

“…A second identical dose of S ‐Y048 was administered 8 hr later. S ‐Y048 and S ‐Y048M were measured in blood samples (2 ml) taken after various times by reversed‐phase HPLC as described previously (Ye et al, ).…”

“…The following were prepared by total chemical synthesis:5‐oxo‐ETE (Khanapure et al, ), racemic 230 (Gore et al, ), racemic 264 (Reddy et al, ), and S ‐Y048 (Ye et al,). The sources of the following reagents were: Streptavidin‐AP, acetoxymethyl ester of fluo‐3, Pluronic F‐127, and N‐(7‐nitrobenz‐2‐oxa‐1,3‐diazol‐4‐yl)phallacidin (NBD‐phallacidin), alum (Imject Alum Adjuvant) (Thermo Fisher Scientific Inc, Waltham, MA, USA); Fast Red (SIGMAFAST Fast RedTR/Naphthol AS‐MX tablets, chromotrope 2R, and Dextran 500 (Sigma Aldrich Canada, Oakville, ON, Canada), hematoxylin (Canadawide Scientific, Ottawa, ON, Canada); Dako Universal Blocking solution (Agilent, Santa Clara, CA, USA).…”

“…The synthetic compound was found to have equivalent potency to S-Y048 in inhibiting 5-oxo-ETE-induced calcium mobilization (Ye et al, 2019).…”

“…Further modification led to our most potent antagonist, the S ‐enantiomer of Y048 (i.e. S ‐Y048 ), which has an in vitro IC 50 of about 20 pM in inhibiting 5‐oxo‐ETE‐induced calcium mobilization in human neutrophils (Ye et al, ). S ‐Y048 is selective for the OXE receptor and does not affect the responses of other relevant receptors to their ligands, including CCR3 (eotaxin), the BLT1 receptor (leukotriene B4) and the DP2 receptor (prostaglandin D2).…”

“…This compound is formed by the stereospecific hydroxylation of the methylene group of S ‐Y048 α to the indole. The synthetic compound was found to have equivalent potency to S ‐Y048 in inhibiting 5‐oxo‐ETE‐induced calcium mobilization (Ye et al, ).…”