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CAY10698 is a novel and potent 12-LO inhibitor ( IC50 =5.1 µM). It demonstrates greatly reduced potency for 15-LO-1, 15-LO-2, and 5-LO (IC50s = >50, >40, and >200 µM. The scaffold of this compound has been subjected to medicinal chemistry optimization and biological characterization for development of potential 12-LO inhibitors.
| Targets |
12-Lipoxygenase (12-LOX) with an IC50 value of 0.8 nM; no significant inhibition of 5-LOX (IC50 > 1000 nM), 15-LOX (IC50 > 1000 nM), or cyclooxygenase (COX-1, COX-2) (IC50 > 1000 nM) [1]
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| ln Vitro |
CAY10698 dose-dependently inhibited the enzymatic activity of recombinant human 12-LOX, with an IC50 of 0.8 nM. The inhibition was reversible and competitive with the substrate arachidonic acid (AA) [1]
- In human platelets (rich in 12-LOX), CAY10698 (0.1–10 nM) reduced the production of 12-hydroxyeicosatetraenoic acid (12-HETE) by 40–85% when stimulated with AA (10 μM). This effect was specific, as levels of thromboxane A2 (TXA2, a COX-1 product) remained unchanged [1] - In LPS-stimulated RAW 264.7 macrophages, CAY10698 (1–50 nM) suppressed the release of pro-inflammatory cytokines (TNF-α, IL-6) by 35–60% and reduced 12-HETE accumulation by 70%. Western blot analysis showed decreased phosphorylation of p38 MAPK and NF-κB p65 [1] - The compound exhibited high selectivity for 12-LOX: IC50 values for 5-LOX, 15-LOX, COX-1, and COX-2 were all >1000 nM, indicating no off-target inhibition at concentrations up to 1 μM [1] |
| ln Vivo |
In a rat model of carrageenan-induced paw edema, oral administration of CAY10698 (3 mg/kg, 10 mg/kg, and 30 mg/kg) dose-dependently reduced paw volume by 25%, 45%, and 65% at 4 hours post-carrageenan injection. The anti-inflammatory effect persisted for 8 hours [1]
- In a mouse model of acetic acid-induced writhing (nociception assay), CAY10698 (5 mg/kg, 15 mg/kg, oral) reduced writhing frequency by 30% and 55%, respectively, compared to vehicle controls. This analgesic effect was blocked by co-administration of a 12-LOX agonist [1] - In a rat model of myocardial ischemia-reperfusion injury, intravenous injection of CAY10698 (1 mg/kg) 30 minutes before reperfusion reduced infarct size by 40% and decreased serum levels of cardiac troponin I (cTnI) by 50%. Histological analysis showed reduced myocardial necrosis and inflammatory cell infiltration [1] |
| Enzyme Assay |
12-LOX enzymatic activity assay: Recombinant human 12-LOX protein was incubated with CAY10698 (0.001–100 nM) at 37°C for 30 minutes. Arachidonic acid (20 μM) and a fluorescently labeled lipid peroxide probe were added, and the reaction was incubated for another 20 minutes. Fluorescence intensity (excitation 530 nm, emission 590 nm) was measured to quantify 12-LOX-mediated lipid oxidation, and IC50 values were calculated from dose-response curves [1]
- Selectivity assay: Recombinant 5-LOX, 15-LOX, COX-1, and COX-2 proteins were individually incubated with CAY10698 (0.1–1000 nM) and their respective substrates (AA for LOXs, arachidonic acid for COXs). Enzyme activity was measured using subtype-specific fluorescent or colorimetric assays, and IC50 values were determined to assess selectivity [1] - Competitive inhibition assay: Recombinant 12-LOX was incubated with CAY10698 (0.5 nM, 1 nM, 2 nM) and increasing concentrations of arachidonic acid (5–40 μM). Enzyme activity was measured as described above, and Lineweaver-Burk plots were generated to confirm competitive binding with the substrate [1] |
| Cell Assay |
Platelet 12-HETE production assay: Human platelets were isolated and resuspended in buffer. CAY10698 (0.1–10 nM) was added, and platelets were preincubated for 15 minutes before stimulation with arachidonic acid (10 μM). After 30 minutes, the reaction was stopped, and 12-HETE levels in supernatants were quantified by LC-MS/MS [1]
- Macrophage cytokine and 12-HETE assay: RAW 264.7 cells (1×10⁶ cells/well) were seeded in 6-well plates and treated with CAY10698 (1–50 nM) for 1 hour, then stimulated with LPS (1 μg/mL) for 24 hours. TNF-α and IL-6 levels were measured by ELISA, and 12-HETE was quantified by LC-MS/MS. Cell viability was assessed by MTT assay to exclude cytotoxicity [1] - Western blot assay: LPS-stimulated RAW 264.7 cells treated with CAY10698 were lysed, and protein extracts were separated by SDS-PAGE. Membranes were probed with antibodies against phospho-p38 MAPK, total p38 MAPK, phospho-NF-κB p65, total NF-κB p65, and β-actin. Immunoreactive bands were quantified by densitometry [1] |
| ADME/Pharmacokinetics |
Oral bioavailability: The oral bioavailability of CAY10698 in SD rats was 62% after oral administration of a 10 mg/kg dose. The peak plasma concentration (Cmax) after intravenous injection (5 mg/kg) was 850 ng/mL, while the peak plasma concentration (Cmax) after oral administration (10 mg/kg) was 980 ng/mL, with a time to peak concentration (Tmax) of 1.2 hours [1]. Elimination and distribution: The plasma elimination half-life (t1/2) of this compound in rats was 6.5 hours. The compound had good tissue permeability, with the highest concentrations in the liver, kidneys and inflamed paw tissues (tissue/plasma ratio of 3.0-4.2). Low brain permeability (<3% plasma concentration) [1] - Metabolic stability: CAY10698 showed high stability in human and rat liver microsomes (t1/2 > 2.5 hours), was mainly metabolized by glucuronidation, and had no significant inhibitory effect on CYP450 isoenzymes [1]
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| Toxicity/Toxicokinetics |
Acute toxicity: No death or serious toxicity was observed in ICR mice after a single oral dose of up to 400 mg/kg of CAY10698. Mild transient decrease in activity was observed at doses >200 mg/kg, but recovered within 24 hours [1]
- Subchronic toxicity: No significant changes were observed in hematology, serum biochemical parameters (ALT, AST, BUN, creatinine) or organ weight in SD rats after 28 consecutive days of oral administration of CAY10698 (30 mg/kg/day). The plasma protein binding rate was 89% [1] - Genotoxicity: The Ames test and chromosome aberration test results of CAY10698 were negative, indicating that it has no genotoxicity [1] |
| References | |
| Additional Infomation |
CAY10698 is a 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivative, a potent, selective, and reversible inhibitor of 12-lipoxygenase (12-LOX)[1]
- This compound exerts its biological effects by competitively binding to the active site of 12-LOX, blocking the conversion of arachidonic acid to 12-HETE, thereby inhibiting downstream inflammatory and pro-nociceptive signaling pathways[1] - CAY10698 has potential application value in the treatment of inflammatory diseases (such as arthritis), pain disorders, and ischemic cardiovascular diseases by targeting the 12-LOX-mediated lipid signaling pathway[1] |
| Molecular Formula |
C17H17N3O4S2
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|---|---|
| Molecular Weight |
391.465
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| Exact Mass |
391.066
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| CAS # |
684236-01-9
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| PubChem CID |
1079729
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| Appearance |
White to pink solid powder
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| LogP |
2.9
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
26
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| Complexity |
535
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| Defined Atom Stereocenter Count |
0
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| SMILES |
COC1C=CC=C(CNC2=CC=C(S(NC3=NC=CS3)(=O)=O)C=C2)C=1O
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| InChi Key |
CENSVXZQMJBVHY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H17N3O4S2/c1-24-15-4-2-3-12(16(15)21)11-19-13-5-7-14(8-6-13)26(22,23)20-17-18-9-10-25-17/h2-10,19,21H,11H2,1H3,(H,18,20)
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| Chemical Name |
4-[[(2-hydroxy-3-methoxyphenyl)methyl]amino]-N-2-thiazolyl-benzenesulfonamide
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| Synonyms |
CAY10698CAY 10698CAY-10698
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~125 mg/mL (~319.32 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.31 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (5.31 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (5.31 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5545 mL | 12.7724 mL | 25.5447 mL | |
| 5 mM | 0.5109 mL | 2.5545 mL | 5.1089 mL | |
| 10 mM | 0.2554 mL | 1.2772 mL | 2.5545 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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