S‐Y048
S-Y048 is an orally active OXE receptor-selective antagonist with picomolar-level IC50 values (0.02-30 nM) and pIC50 values of (10.47-10.81) against human receptors. S-Y048 selectively blocks the 5-oxo-ETE signaling pathway, inhibits actin polymerization, calcium mobilization, leukocyte migration, as well as allergen-induced leukocyte infiltration in skin and lung tissues, and reduces mucin-producing bronchial epithelial cells. S-Y048 undergoes benzyl, N-methyl and α-hydroxylation reactions to form metabolites in monkeys. S-Y048 can be used in research related to asthma, allergic asthma, allergic eosinophilic diseases, atopic dermatitis and allergic rhinitis.
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- CAS No.: 2020058-38-0
- Formule: C27H31Cl2NO3
- Masse moléculaire:488.45
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Activité biologique
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Chemical Information
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Activité biologique
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OXE Receptor 0.02-30 nM (IC50) |
OXE Receptor 10.47-10.8 (pIC50) |
S-Y048 potently inhibits 5-oxo-ETE-induced calcium mobilization in human neutrophils with an IC50 of 20 pM, and exerts insurmountable antagonistic effects at picomolar concentrations (pIC50 = 10.81)[2][4].
S-Y048 inhibits 5-oxo-ETE-induced actin polymerization (IC50 = 340 pM) and mixed leukocyte migration (IC50 = 30 nM) in human eosinophils[1][3].
S-Y048 completely blocks 5-oxo-ETE-induced calcium mobilization, actin polymerization, and cell migration in rhesus monkey eosinophils and neutrophils, with an IC50 of 0.34 nM for actin polymerization, which is comparable to its potency in human cells; the IC50 for migration of unseparated leukocytes is 30 nM[1][3].
S-Y048 does not inhibit actin polymerization induced by PGD2, LTB4, or eotaxin, indicating its OXE receptor-targeting specificity[1][4].
S-Y048 is metabolized in cynomolgus monkey liver microsomes via benzyl hydroxylation and N-methyl hydroxylation/demethylation pathways, with an overall rate lower than that of S-C025; its ω-hydroxylation reaction has a Km of 24 μM and a Vmax of 0.41 pmol/min/μg protein, and the rate is significantly slower than that of S-230[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
S-Y048 (5 mg/kg; administered via nasogastric tube; repeated dosing at 8 h after the first administration) potently inhibits allergen-induced pulmonary inflammation and mucin production in a rhesus monkey model of allergic asthma[2].
S-Y048 (5 mg/kg; administered via nasogastric tube; repeated administration at 8 h after the first dose) inhibits allergen-induced skin eosinophilia in rhesus monkeys[2].
S-Y048 (5 mg/kg; administered via nasogastric tube; repeated dosing 8 h after the first administration) is mainly metabolized via α-hydroxylation to form αS-hydroxy-S-Y048 in cynomolgus monkeys, while the benzyl hydroxylation/oxidation and N-demethylation pathways play only minor roles[2].
S-Y048 (5-10 mg/kg, administered via oral gavage with an 8 h interval between two doses) significantly inhibits 5-oxo-ETE- and HDM-induced skin eosinophilia in HDM-sensitized rhesus monkeys, and the 5 mg/kg dose completely blocks the response triggered by 5-oxo-ETE[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Male rhesus monkeys (7-8 years old, 7.5-16.7 kg) were sensitized by subcutaneous injections of HDM (60 μg protein with 1 mg alum, 1 mL per injection, once every two weeks; the naïve group received 7 injections, whereas the skin study group had been pre-sensitized with 4 injections), and pulmonary inflammation was induced by subsequent aerosolized HDM challenge (1.5 mg per exposure, 5-15 min)[1]
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Dosage:10 mg/kg
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Administration:nasogastric intubation; two doses 8 h apart (1 h before and 7 h after aerosolized HDM challenge)
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Result:Reduced HDM-induced BAL neutrophil elevation by 77% (from a 24-fold increase in vehicle-treated animals to a 6-fold increase, P < 0.05).
Reduced HDM-induced BAL eosinophil elevation by 52% (from a 4.5-fold increase to a 3-fold increase, P < 0.05; excluding an outlier, inhibition rose to 80%, P < 0.05).
Reduced lung tissue eosinophil counts by nearly 50% (P < 0.05).
Reduced lung tissue neutrophil counts by about 50% (P < 0.05).
Reduced AB/PAS-positive mucin-containing bronchial cells by about 40% (P < 0.01).
Reduced MUC5AC-positive bronchial cells by about 60% (P < 0.05).
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Animal Model:Female cynomolgus monkeys (weighing 2.5-3.5 kg)[2]
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Dosage:5 mg/kg
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Administration:nasogastric intubation; repeated dose 8 h after initial dose
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Result:Identified αS-hydroxy-S-Y048 as the major circulating metabolite.
Detected minor microsomal-derived metabolites including benzylic hydroxylation/oxidation products (Aᵧ, Bᵧ, Fᵧ) and N-demethylation product Dᵧ.
Detected small amounts of αS-hydroxy-ω-oxo-S-Y048 (Xᵧ).
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Animal Model:Rhesus monkeys[2]
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Dosage:5 mg/kg
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Administration:nasogastric intubation; repeated dose 8 h after initial dose
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Result:Strongly inhibited house dust mite-induced infiltration of eosinophils and neutrophils into lung tissue and airway lumen.
Reduced the numbers of mucin-containing bronchial epithelial cells.
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Animal Model:Rhesus monkeys[2]
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Dosage:5 mg/kg
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Administration:nasogastric intubation; repeated dose 8 h after initial dose
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Result:Inhibited the infiltration of eosinophils into the skin in response to intradermal house dust mite allergen challenge.
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Animal Model:Captive-bred adult male (10.1-16.7 kg; HDM-sensitized allergic skin inflammation model)[3]
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Dosage:5 mg/kg; 10 mg/kg
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Administration:nasogastric intubation; two doses 8 hr apart
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Result:Completely inhibited 5-oxo-ETE-induced dermal eosinophilia, reducing eosinophil volume fractions from a vehicle-treated mean of 29 × 10-5 to levels matching vehicle-only injection sites (5 mg/kg dose).
Significantly inhibited 5-oxo-ETE-induced eosinophilia, reducing eosinophil volume fractions in 5 of 6 monkeys (10 mg/kg dose).
Significantly inhibited HDM-induced dermal eosinophilia, reducing mean eosinophil volume fractions from a vehicle-treated mean of ~15 × 103 to ~8 × 103 (5 mg/kg dose).
Significantly inhibited HDM-induced dermal eosinophilia, reducing mean eosinophil volume fractions from a vehicle-treated mean of ~15 × 103 to ~7 × 103 (10 mg/kg dose).
Reached ~20 μM within 1 hr of the first 5 mg/kg dose, peaked at ~30 μM after the second dose, and declined to ~12 μM at 24 hr; active metabolite S-Y048M reached ~5 μM at 24 hr.
Reached ~15 μM within 1 hr of the first 10 mg/kg dose, peaked at ~20 μM after the second dose, and remained elevated at 24 hr.
Chemical Information
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CAS No. 2020058-38-0
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Masse moléculaire 488.45
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Formule C27H31Cl2NO3
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SMILES
OC(C[C@@H](C)CC(C(C1=C2)=C(CCCCCCC3=CC(Cl)=CC=C3)N(C)C1=CC=C2Cl)=O)=O
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
[1]. Cossette C, et al. Targeting the OXE receptor with a selective antagonist inhibits allergen-induced pulmonary inflammation in non-human primates. British journal of pharmacology. 2022 Jan;179(2):322-336. [Content Brief]
[2]. Cossette C, et al. Metabolism of anti-inflammatory OXE (oxoeicosanoid) receptor antagonists by nonhuman primates. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2022 May 01;172:106144. [Content Brief]
[3]. Miller LA, et al. Inhibition of allergen-induced dermal eosinophilia by an oxoeicosanoid receptor antagonist in non-human primates. British journal of pharmacology. 2020 Jan;177(2):360-371. [Content Brief]
[4]. Ye Q, et al. Novel highly potent OXE receptor antagonists with prolonged plasma lifetimes that are converted to active metabolites in vivo in monkeys. British journal of pharmacology. 2020 Jan;177(2):388-401. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
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