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| Targets |
YQ128 targets the NLRP3 inflammasome. In J774A.1 cells stimulated with LPS/ATP, it inhibits IL-1β release with an IC50 of 0.30 ± 0.01 μM. In mouse peritoneal macrophages, the IC50 is 1.59 ± 0.60 μM. It does not significantly inhibit NLRC4 or AIM2 inflammasomes at 10 μM. [1]
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| ln Vitro |
At an IC50 of 1.59 µM, YQ128 (0.3-100 µM; 30 minutes) dose-dependently inhibits the release of IL-1β from peritoneal macrophages after an LPS/ATP challenge [1]. YQ128 (20 µM; 2 hours) does not appear to be toxic to hCMEC/D3 cells [1].
YQ128 inhibited IL-1β production in J774A.1 cells with an IC50 of 0.30 ± 0.01 μM upon LPS/ATP stimulation. [1] In mouse peritoneal macrophages, YQ128 dose-dependently suppressed IL-1β release with an IC50 of 1.59 ± 0.60 μM. [1] At 10 μM, YQ128 did not significantly inhibit NLRC4 or AIM2 inflammasomes in J774A.1 cells (stimulated with flagellin or poly(dA:dT), respectively), indicating selective NLRP3 inhibition. [1] In hCMEC/D3 cells (human BBB model), YQ128 at 20 μM showed no significant cytotoxicity after 2 h as measured by Live/Dead assay. [1] |
| ln Vivo |
YQ128 (iv; 20 mg/kg) has an intermediate terminal plasma half-life (t1/2) of 6.6 hours following intravenous administration [1]. With a tmax of 12 hours and a cmax of 73 ng/mL, respectively, YQ128 (oral; 20 mg/kg) demonstrated delayed gastrointestinal absorption. The estimated oral bioavailability (Foral) is 10% [1]. With a rapid total clearance (CLtot) of 41 mL/min/kg and a steady-state volume of distribution (Vdss) of 8.5 L/kg, YQ128 demonstrates a wide extravascular distribution[1]. It has been demonstrated that YQ128 (10 mg/kg) in C57BL/6 mice induces the production of IL-1β in an NLRP3-dependent manner [1].
In C57BL/6 mice challenged with LPS (50 mg/kg, ip), pretreatment with YQ128 (10 mg/kg, ip) significantly reduced serum IL-1β levels but did not affect TNF-α levels, demonstrating selective in vivo NLRP3 engagement. [1] In nlrp3-/- mice (LPS 25 mg/kg, ip), YQ128 (10 mg/kg, ip) showed no inhibition of TNF-α production, further confirming selectivity for NLRP3. [1] Oral administration of YQ128 (20 mg/kg) in C57BL/6 mice resulted in brain concentrations of 21.3, 20.5, and 6.6 ng/g at 0.5, 1, and 4 h post-dose, respectively, indicating blood-brain barrier penetration. Brain-to-plasma ratios increased with time (0.077, 0.36, 0.82 at 0.5, 1, 4 h). [1] |
| Cell Assay |
Cell viability assay [1]
Cell Types: mouse peritoneal macrophages Tested Concentrations: 0.3, 1.0, 3.0, 10, 30, 100 µM Incubation Duration: 30 minutes Experimental Results: Inhibition of IL- release from peritoneal macrophages after LPS/ATP challenge 1β IC50 is 1.59 µM. J774A.1 cells were plated in 96-well plates (1×10^5 cells/well) for 24 h, primed with LPS (1 μg/mL) for 4.5 h, then treated with YQ128 at various concentrations (0.1–10 μM) for 30 min. ATP (5 mM) was added simultaneously to activate NLRP3. After 30 min, supernatants were collected and IL-1β measured by ELISA. [1] Mouse peritoneal macrophages were harvested from C57BL/6 mice injected with 3% thioglycolate (1 mL ip). After 3 days, peritoneal cells were collected, adherent macrophages were treated similarly to J774A.1 cells, and IL-1β was measured by ELISA. [1] For NLRC4 and AIM2 selectivity assays, J774A.1 cells were treated with LPS (1 μg/mL) and YQ128 (10 μM) for 1 h, then stimulated with flagellin (1 μg/mL) for 6 h or poly(dA:dT) (4 μg/mL) for 8 h. Supernatants were collected and IL-1β measured by ELISA. [1] hCMEC/D3 cells (passage 25-35) were seeded on transwell filters (150,000 cells/well, 3.0 μm pores) and cultured for 5 days. On day 5, YQ128 (20 μM in DPBS with 0.01% DMSO) was added to apical or basolateral side. Samples were collected at 5, 10, 15, 30, 45, 60 min and quantified by HPLC. Apparent permeability (Papp) was calculated. Cytotoxicity was assessed using Live/Dead kit after 2 h treatment. [1] |
| Animal Protocol |
Animal/Disease Models: SD (SD (Sprague-Dawley)) rat (200-250 g) [1]
Doses: 20 mg/kg (pharmacokinetic/PK/PK analysis) Route of Administration: intravenous (iv) (iv)injection Experimental Results: After intravenous (iv) (iv)administration, the intermediate terminal plasma half-life ( t1/2) is 6.6 hrs (hrs (hours)). C57BL/6 mice (n=4 per group) were pretreated with YQ128 (10 mg/kg, ip) or MCC950 (10 mg/kg, ip) 1 h before ip injection of LPS (50 mg/kg) or PBS. Serum levels of IL-1β and TNF-α were measured by ELISA 2.5 h after LPS challenge. [1] nlrp3-/- mice (n=3 per group) were injected ip with LPS (25 mg/kg) after same pretreatment, and serum TNF-α was measured. [1] For BBB penetration, C57BL/6 mice (n=3 per time point) received YQ128 orally (20 mg/kg, single dose). Plasma and perfused brain tissues were collected at 0.5, 1, and 4 h, and analyzed by LC-MS/MS. [1] For PK studies, Sprague-Dawley rats (200-250 g, n=3) received YQ128 at 20 mg/kg via iv (bolus) and oral (suspension in 10% Cremophor EL in PBS) administration. Plasma samples were collected at 0.08, 0.17, 0.25, 0.5, 0.75, 1, 2, 4, 8, 12, 24 h and analyzed by LC-MS/MS. [1] |
| ADME/Pharmacokinetics |
In rats, after iv administration of YQ128 (20 mg/kg), the steady-state volume of distribution (Vdss) was 8.5 L/kg, total clearance (CLtot) was 41 mL/min/kg, and terminal plasma half-life (t1/2) was 6.6 h. [1]
After oral administration (20 mg/kg, 10% Cremophor EL in PBS), Tmax was 12 h, Cmax was 73 ng/mL, and oral bioavailability (Foral) was estimated to be 10%, suggesting poor GI solubility/permeability and/or high first-pass effects. [1] In hCMEC/D3 cell permeability assay, the apical-to-basolateral Papp of YQ128 was 5.21±0.56×10^-6 cm/s, and basolateral-to-apical Papp was 1.11±0.12×10^-6 cm/s, giving an efflux ratio of 0.22, indicating it is not likely subject to active efflux (e.g., P-glycoprotein). [1] |
| Toxicity/Toxicokinetics |
In hCMEC/D3 cells, YQ128 at 20 μM did not show significant cytotoxicity after 2 h as measured by Live/Dead assay. [1]
No other toxicity data (e.g., LD50, hepatotoxicity, etc.) are reported in this paper. [1] |
| References | |
| Additional Infomation |
YQ128 is N-(5-chloro-2-propoxybenzyl)-N-(4-(N-(prop-2-yn-1-yl)sulfamoyl)phenethyl)-2-(thiophen-3-yl)acetamide (compound 17). It selectively inhibits the NLRP3 inflammasome without affecting NLRC4 or AIM2, and without interfering with the upstream LPS priming step. The compound penetrates the blood-brain barrier and is not a substrate for efflux transporters. It shows a half-life of 6.6 h in rats but low oral bioavailability (10%). The compound is intended for development as a therapeutic for Alzheimer's disease, multiple sclerosis, and traumatic brain injury. [1]
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| Molecular Formula |
C27H29CLN2O4S2
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|---|---|
| Molecular Weight |
545.109
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| Exact Mass |
544.125
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| Elemental Analysis |
C, 59.49; H, 5.36; Cl, 6.50; N, 5.14; O, 11.74; S, 11.76
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| CAS # |
2454246-18-3
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| PubChem CID |
139600339
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
705.8±70.0 °C at 760 mmHg
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| Flash Point |
380.6±35.7 °C
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| Vapour Pressure |
0.0±2.2 mmHg at 25°C
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| Index of Refraction |
1.606
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| LogP |
5.47
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
13
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| Heavy Atom Count |
36
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| Complexity |
832
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C=CC(=C(C=1)CN(C(CC1=CSC=C1)=O)CCC1C=CC(=CC=1)S(NCC#C)(=O)=O)OCCC
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| InChi Key |
SFPYRFRNYALLHS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H29ClN2O4S2/c1-3-13-29-36(32,33)25-8-5-21(6-9-25)11-14-30(27(31)17-22-12-16-35-20-22)19-23-18-24(28)7-10-26(23)34-15-4-2/h1,5-10,12,16,18,20,29H,4,11,13-15,17,19H2,2H3
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| Chemical Name |
N-(5-chloro-2-propoxybenzyl)-N-(4-(N-(prop-2-yn-1-yl)sulfamoyl)phenethyl)-2-(thiophen-3-yl)acetamide
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| Synonyms |
YQ-128YQ128 YQ 128
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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 |
| 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 : ~250 mg/mL (~458.62 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.82 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 (3.82 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8345 mL | 9.1725 mL | 18.3449 mL | |
| 5 mM | 0.3669 mL | 1.8345 mL | 3.6690 mL | |
| 10 mM | 0.1834 mL | 0.9172 mL | 1.8345 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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