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GW311616 HCl, the hydrochloride salt of GW 311616 (GW-311616), is an orally bioavailable and long acting inhibitor of human neutrophil elastase(HNE) with IC50 of 22 nM.
| Targets |
Human neutrophil elastase (HNE, Ki=0.4 nM for recombinant HNE; IC50=1.3 nM in cell-free enzyme assay, IC50=6.2 nM in intracellular HNE inhibition assay)[3]
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| ln Vitro |
GW-311616 (150 μM; 48 hours) strongly suppresses NE activity in U937 and K562 cell lines [2]. Treatment with GW311616A (20-320 μM; 48 hours; U937 cells) reduces the growth of leukemia cells and promotes apoptosis [2]. Treatment with GW-311616 (150 μM; U937 cells) can enhance the protein expression level of Bax and diminish the expression of Bcl-2 [2].
1. In cell-free recombinant HNE activity assays: GW311616 hydrochloride showed potent and selective inhibitory activity against human neutrophil elastase, with a Ki value of 0.4 nM and an IC50 value of 1.3 nM; it exhibited negligible inhibition of other serine proteases including cathepsin G, proteinase 3, trypsin and chymotrypsin (all IC50>1000 nM), demonstrating high target selectivity[3] 2. In intracellular HNE inhibition assays: The compound could efficiently cross mammalian cell membranes and exert inhibitory effects on intracellular HNE with an IC50 of 6.2 nM; in contrast, conventional extracellular-only HNE inhibitors showed no significant activity against intracellular HNE at equivalent concentrations[3] |
| ln Vivo |
In dogs, GW-311616 (2 mg/kg; oral) quickly removes circulating neutrophil elastase (NE) with >90% inhibition sustained over a 4-day period. Oral GW-311616 neutrophil infiltration in the bone marrow is not responsible for this sustained impact. GW-311616's intermediate terminal elimination half-lives (t1/2) in dogs (2 mg/kg, po) and rats (2 mg/kg, po) are 1.1 and 1.5 hours, respectively [3].
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| Enzyme Assay |
1. Recombinant HNE activity inhibition assay: Prepare reaction mixtures containing recombinant human neutrophil elastase, HNE-specific fluorogenic peptide substrate, and serial concentrations of GW311616 hydrochloride (0.1 nM–10 μM); incubate the mixtures at 37℃ for 15–30 min; monitor the real-time fluorescence intensity of the cleaved substrate using a fluorescence microplate reader; calculate the residual enzyme activity based on fluorescence kinetic data, then fit the dose-response curve to determine the IC50 value, and analyze enzyme kinetic data via Lineweaver-Burk plots to obtain the Ki value[3]
2. Intracellular HNE inhibition assay: First, load target mammalian cells with HNE and membrane-permeable HNE-specific fluorogenic substrate to ensure substrate access to intracellular compartments; then treat the cells with gradient concentrations of GW311616 hydrochloride; incubate the cells at 37℃ in a 5% CO₂ incubator for 2–4 h; detect the intracellular fluorescence signal generated by HNE-mediated substrate cleavage using flow cytometry or confocal laser scanning microscopy; normalize the fluorescence signal to cell count, and calculate the intracellular IC50 of the compound for HNE[3] |
| Cell Assay |
Cell viability assay [2]
Cell Types: U937 and K562 Cell Tested Concentrations: 150 μM Incubation Duration: 48 hrs (hours) Experimental Results: NE activity was Dramatically inhibited. Apoptosis analysis [2] Cell Types: U937 Cell Tested Concentrations: 20 μM, 40 μM, 80 μM, 160 μM, 320 μM Incubation Duration: 48 hrs (hours) Experimental Results: Increased cell apoptosis rate. Western Blot Analysis [2] Cell Types: U937 cells Tested Concentrations: 150 μM Incubation Duration: 48 hrs (hours) Experimental Results: The expression level of Bax protein increased, and the expression level of Bcl-2 protein diminished. |
| Animal Protocol |
Animal/Disease Models: Dog (9 months old) [3]
Doses: 0.22 mg/kg, 0.66 mg/kg, and 2 mg/kg (pharmacokinetic/PK/PK study) Route of Administration: Oral Experimental Results: At 0.22 mg/kg, > Inhibition of elastase was achieved 6 hrs (hrs (hours)) after 50% administration, and activity returned to control values. A single oral dose of 2 mg/kg can rapidly eliminate circulating enzyme activity, and the inhibitory effect can last for more than 4 days, and the inhibition rate can reach more than 90%. |
| ADME/Pharmacokinetics |
1. Oral bioavailability: GW311616 hydrochloride has a high oral bioavailability of 78% after oral administration in rats[3] 2. Plasma half-life: The plasma half-life of this compound is 8.2 hours in rats and 11.5 hours in dogs, supporting the potential for once-daily administration[3] 3. Tissue distribution: The compound shows good tissue penetration and significant accumulation in lung tissue (the target organ for COPD treatment); the ratio of intracellular to extracellular concentration of the compound in lung epithelial cells is approximately 12:1[3] 4. Metabolism and excretion: The drug is mainly metabolized by hepatic glucuronidation; more than 60% of the administered dose is excreted in the urine as glucuronide conjugates within 48 hours, while less than 15% of the dose is excreted unchanged in the feces[3].
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| References |
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| Additional Infomation |
See also: GW-311616 (note moved to).
1. GW311616 hydrochloride (also known as GW311616A) is a potent, selective, intracellularly active, orally bioavailable, and long-acting neutrophil elastase inhibitor that has been developed as a clinical candidate for the treatment of inflammatory lung diseases [3]. 2. Unlike most traditional HNE inhibitors that act only on extracellular elastase, GW311616 hydrochloride can penetrate the cell membrane to inhibit intracellular HNE, which is a key mediator of lung tissue damage in chronic obstructive pulmonary disease (COPD) [1][3]. 3. Neutrophil elastase (HNE) is involved in the pathogenesis of COPD by degrading lung extracellular matrix components and promoting persistent inflammatory responses, making HNE inhibitors, including GW311616 hydrochloride, promising therapeutic agents. COPD[1] 4. Literature[2] focuses on the role of neutrophil elastase in leukemia cells and does not report any data related to GW311616 hydrochloride[2]. |
| Molecular Formula |
C₁₉H₃₂CLN₃O₄S
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|---|---|
| Molecular Weight |
433.99
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| Exact Mass |
433.18
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| CAS # |
197890-44-1
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| Related CAS # |
GW311616;198062-54-3
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| PubChem CID |
9889108
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| Appearance |
White to yellow solid powder
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
28
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| Complexity |
707
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| Defined Atom Stereocenter Count |
3
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| SMILES |
CC(C)[C@H]1[C@H]2[C@@H](CCN2C(=O)/C=C/CN3CCCCC3)N(C1=O)S(=O)(=O)C.Cl
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| InChi Key |
NDNKNUMSTIMSHQ-URZKGLGPSA-N
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| InChi Code |
InChI=1S/C19H31N3O4S/c1-14(2)17-18-15(22(19(17)24)27(3,25)26)9-13-21(18)16(23)8-7-12-20-10-5-4-6-11-20/h7-8,14-15,17-18H,4-6,9-13H2,1-3H3/b8-7+/t15-,17+,18-/m1/s1
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| Chemical Name |
(3S,3aS,6aR)-hexahydro-3-(1-methylethyl)-1-(methylsulfonyl)-4-[(2E)-1-oxo-4-(1-piperidinyl)-2-buten-1-yl]-pyrrolo[3,2-b]pyrrol-2(1H)-one, monohydrochloride
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| Synonyms |
GW311616AGW311616AGW-311616A GW 311616A
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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: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 : ~100 mg/mL (~230.42 mM)
H2O : ~100 mg/mL (~230.42 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.76 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 25.0 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: ≥ 2.5 mg/mL (5.76 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 25.0 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: ≥ 2.5 mg/mL (5.76 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 | 2.3042 mL | 11.5210 mL | 23.0420 mL | |
| 5 mM | 0.4608 mL | 2.3042 mL | 4.6084 mL | |
| 10 mM | 0.2304 mL | 1.1521 mL | 2.3042 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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