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Purity: ≥98%
Alvelestat (formerly also known as MPH966; AZD9668) is a novel, potent, orally bioavailable, and highly selective inhibitor of neutrophil elastase (NE) with potential anti-inflammatory properties is Alvelestat (previously also known as MPH966; AZD9668). Compared to other serine proteases, it is at least 600-fold more selective and inhibits neutrophil elastase with IC50 and Ki of 12 nM and 9.4 nM, respectively.
| Targets |
neutrophil elastas (pIC = 7.9 nM); neutrophil elastas (Ki = 9.4 nM); neutrophil elastas (Kd = 9.5 nM)
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|---|---|
| ln Vitro |
AZD9668 suppresses NE activity in the supernatant of primed, stimulated cells as well as on the surface of stimulated polymorphonuclear cells and plasma NE activity in whole blood stimulated with zymosan.[1]
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| ln Vivo |
AZD9668 (p.o.) protects against human NE-induced lung injury in mice and rats. A mouse model of smoke-induced airway inflammation shows that AZD9668 dramatically lowers BAL neutrophil counts and BAL IL-1β levels. AZD9668 inhibits the remodeling of the small airway wall and enlargement of the airspace in guinea pigs exposed to tobacco smoke over an extended period of time in a chronic smoke model.[1]
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| Enzyme Assay |
AZD9668 demonstrated a strong inhibition of NE activity and a high binding affinity (KD = 9.5 nM) for human NE. For human NE, AZD9668's computed pIC50 (IC50) and Ki values were 7.9 (12 nM) and 4.9 nM, respectively. AZD9668 and NE exhibited a swiftly reversible interaction, in contrast to previous NE inhibitors. In comparison to other neutrophil-derived serine proteases, AZD9668 exhibited a high degree of selectivity for NE.
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| Cell Assay |
AZD9668 reduced plasma NE activity in whole blood stimulated with zymosan in cell-based experiments. In human polymorphonuclear cells that were isolated, AZD9668 reduced NE activity in the primed, stimulated cell supernatant and on the surface of the stimulated cells. Good crossover potency to NE was demonstrated by AZD9668 from other species.
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| Animal Protocol |
Human NE-induced acute lung injury in mice or rats, guinea pig chronic smoke model.
~10 mg/kg (mice); ~20 mg/kg (rats); ~100 mg/kg (pigs) p.o. |
| References | |
| Additional Infomation |
Alvelestat has been investigated for the basic science of Chronic Obstructive Pulmonary Disease.
Alvelestat is an orally bioavailable, selective and reversible inhibitor of human neutrophil elastase (NE), with potential anti-inflammatory activity. Upon administration, alvelestat binds to and inhibits the activity of human NE. This inhibits NE-mediated inflammatory responses, which may prevent lung inflammation and injury, and may improve lung function associated with NE-induced respiratory diseases. NE, a serine protease released by neutrophils during inflammation, is upregulated in a number of respiratory diseases. |
| Molecular Formula |
C25H22F3N5O4S
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|---|---|
| Molecular Weight |
545.53
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| Exact Mass |
545.134
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| Elemental Analysis |
C, 55.04; H, 4.06; F, 10.45; N, 12.84; O, 11.73; S, 5.88
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| CAS # |
848141-11-7
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| Related CAS # |
Alvelestat tosylate;1240425-05-1
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| PubChem CID |
46861623
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
780.4±60.0 °C at 760 mmHg
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| Flash Point |
425.8±32.9 °C
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| Vapour Pressure |
0.0±2.7 mmHg at 25°C
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| Index of Refraction |
1.628
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| LogP |
0.5
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
38
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| Complexity |
1100
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1C(=O)N(C2C=C(C(F)(F)F)C=CC=2)C(C)=C(C2N(C)N=CC=2)C=1)NCC1C=CC(S(C)(=O)=O)=CN=1
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| InChi Key |
QNQZWEGMKJBHEM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H22F3N5O4S/c1-15-20(22-9-10-31-32(22)2)12-21(23(34)30-13-17-7-8-19(14-29-17)38(3,36)37)24(35)33(15)18-6-4-5-16(11-18)25(26,27)28/h4-12,14H,13H2,1-3H3,(H,30,34)
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| Chemical Name |
6-methyl-5-(2-methylpyrazol-3-yl)-N-[(5-methylsulfonylpyridin-2-yl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide
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| Synonyms |
Alvelestat; AZD 9668; MPH966; MPH 966; AZD9668; AZD-9668; MPH-966
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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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 25 mg/mL (45.83 mM) in 20% DMSO, 60% PEG400, 20% Water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Solubility in Formulation 2: ≥ 2.5 mg/mL (4.58 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.58 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. Solubility in Formulation 4: ≥ 2.5 mg/mL (4.58 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 25.0 mg/mL clear DMSO stock solution to 900 μL corn oil and mix evenly. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8331 mL | 9.1654 mL | 18.3308 mL | |
| 5 mM | 0.3666 mL | 1.8331 mL | 3.6662 mL | |
| 10 mM | 0.1833 mL | 0.9165 mL | 1.8331 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03679598 | Active Recruiting |
Drug: Alvelestat (MPH966) Other: Placebo |
Alpha-1 Antitrypsin Deficiency (AATD) Emphysema or COPD |
University of Alabama at Birmingham |
April 8, 2019 | Phase 2 |
| NCT02669251 | Recruiting | Drug: MPH966 | Chronic Graft vs Host Disease Chronic Graft-Versus-Host Disease |
National Cancer Institute (NCI) |
April 28, 2016 | Phase 1 Phase 2 |
| NCT04539795 | Completed | Drug: Alvelestat Drug: Placebo |
Covid19 | University of Alabama at Birmingham |
January 25, 2021 | Phase 1 Phase 2 |
| NCT03636347 | Completed | Drug: Alvelestat oral tablet - dose 1 Drug: Alvelestat oral tablet - dose 2 |
COPD Emphysema |
Mereo BioPharma | October 29, 2018 | Phase 2 |
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