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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]
The target of YQ128 is the NLRP3 inflammasome. By inhibiting this multiprotein complex, it blocks the activation of caspase-1 and the subsequent maturation and secretion of pro-inflammatory cytokines like IL-1β and IL-18. It does not interfere with IL-1β production by NLRC4 or AIM2 inflammasomes, demonstrating its selectivity for NLRP3. This selectivity is crucial for minimizing off-target effects and understanding the specific role of NLRP3 in disease. |
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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] In vitro, YQ128 dose-dependently suppresses the release of IL-1β from peritoneal macrophages upon LPS/ATP challenge, with an IC50 of 1.59 µM. It shows significant and selective inhibition of IL-1β production but does not affect TNF-α production, confirming its specificity for the NLRP3 inflammasome pathway. At a concentration of 20 µM, YQ128 does not appear to be toxic to hCMEC/D3 cells, indicating a good safety margin in vitro. |
| 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] In vivo, YQ128 (oral; 20 mg/kg) shows delayed gastrointestinal absorption with a tmax and cmax of 12 h and 73 ng/mL, respectively. It exhibits extensive extravascular distribution with a large steady-state volume of distribution (Vdss) of 8.5 L/kg and rapid total clearance (CLtot) of 41 mL/min/kg. The estimated oral bioavailability (Foral) is 10%. In C57BL/6 mice (10 mg/kg), it triggers IL-1β production in a NLRP3-dependent manner. |
| Enzyme Assay |
Non-cellular assays typically involve binding or inhibition studies with purified NLRP3 protein or its components. YQ128's inhibitory effect on NLRP3 ATPase activity can be measured. The IC50 value of 0.30 µM is determined by assessing the compound's ability to inhibit the function of the purified NLRP3 inflammasome complex or its components.
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| 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] J774A.1 macrophages or primary peritoneal macrophages are stimulated with LPS and ATP to activate the NLRP3 inflammasome. Cells are treated with varying concentrations of YQ128, and the levels of IL-1β and TNF-α in the supernatant are measured by ELISA. The compound's selectivity is confirmed by its inhibition of IL-1β but not TNF-α. The IC50 for the inhibition of IL-1β release is determined to be 1.59 µM. |
| 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] In vivo activity is evaluated in mouse models of NLRP3-driven inflammation. YQ128 is administered orally, and its effect on IL-1β production and other inflammatory markers is measured. Pharmacokinetic parameters such as Cmax, Tmax, and clearance are determined from plasma samples. In C57BL/6 mice, YQ128 (10 mg/kg) induces the production of IL-1β in an NLRP3-dependent manner. |
| 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] In rats, YQ128 exhibits a Tmax of 12 hours and a Cmax of 73 ng/mL after oral administration at 20 mg/kg. It has a large volume of distribution (8.5 L/kg) and rapid clearance (41 mL/min/kg), indicating extensive tissue distribution and fast elimination. The compound has an intermediate terminal plasma half-life (t1/2) of 6.6 hours following intravenous administration. |
| 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] YQ128 can cross the blood-brain barrier. This property is important for its potential application in central nervous system (CNS) disorders where NLRP3 inflammasome activation is implicated, such as Alzheimer's disease and multiple sclerosis. Its selectivity for NLRP3 over other inflammasomes suggests a favorable safety profile. |
| 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]
YQ128 is a research tool for studying the role of the NLRP3 inflammasome in various diseases, including inflammatory and neurodegenerative conditions. Its ability to cross the blood-brain barrier makes it a valuable compound for CNS research. It is a potent and selective second-generation inhibitor that is used to investigate the therapeutic potential of targeting the NLRP3 inflammasome. |
| 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
|
| Heavy Atom Count |
36
|
| 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
|
| 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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