Alvelestat

Alvelestat (AZD9668) is an orally active, selective inhibitor of neutrophil elastase. Alvelestat reduces elastase activity, myeloperoxidase release, neutrophil recruitment and activation, and calcium phosphate precipitation; promotes smooth muscle cell colonization and collagen deposition; and inhibits the formation of neutrophil extracellular traps (NETs) as well as NET-derived neutrophil elastase activity. Alvelestat restores endothelial dysfunction, regulates antioxidant factors, improves the expression of endothelial tight junctions, reduces vascular leakage, and accelerates wound healing. Alvelestat prevents pulmonary hemorrhage, matrix protein degradation, airspace enlargement, and small airway wall remodeling; and alleviates cigarette-induced inflammatory responses. Alvelestat inhibits the growth of abdominal aortic aneurysms exacerbated by Porphyromonas gingivalis. Alvelestat can be used in research related to chronic obstructive pulmonary disease, abdominal aortic aneurysm, radiation-induced skin injury, and bronchiectasis^[1][2][3][4]. In Vitro:Alvelestat potently, fully reversibly and selectively inhibits human neutrophil elastase, with at least 100-fold selectivity over other serine proteases, enzymes, receptors and ion channels^[1].
Alvelestat (AZD9668) potently inhibits purified rat neutrophil elastase with an IC₅₀ of approximately 7 nM; it also potently inhibits purified human neutrophil elastase with an IC₅₀ of approximately 8 nM^[2].
Alvelestat (AZD9668) (20 μg/mL; 3 h) potently inhibits NE activity and NET formation in human polymorphonuclear neutrophils (PMNs) stimulated by IR + PMA; it also potently inhibits neutrophil elastase (NE) activity in isolated human neutrophil extracellular traps (NETs)^[3].
Alvelestat binds to purified human neutrophil elastase with high affinity in a rapid and reversible manner (K_D = 9.5 nM), potently inhibits purified human neutrophil elastase (pIC₅₀ = 7.9, IC₅₀ = 12 nM), shows high selectivity over other serine proteases, and exhibits favorable cross-species activity against neutrophil elastase derived from mice, rats, guinea pigs, and dogs^[4].
Alvelestat potently inhibits neutrophil elastase activity in zymosan-stimulated human whole blood (pIC₅₀ = 7.36, IC₅₀ = 44 nM); it also potently inhibits cell-associated neutrophil elastase activity in human polymorphonuclear cells stimulated by LPS and fMLP (pIC₅₀ = 7.31, IC₅₀ = 48 nM)^[4].
Alvelestat potently inhibits the activity of neutrophil elastase released in a burst from Cytochalasin B (HY-16928)-pretreated, fMLP-stimulated human polymorphonuclear cells (pIC₅₀ = 7.30, IC₅₀ = 50 nM)^[4].
Alvelestat (20 μg/mL; 24 h) improves the angiogenic functions (branch point formation and tube length) of HUVECs treated with IR + NET; it restores the endothelial barrier function of IR + NET-treated HUVECs and the expression of tight junction proteins claudin-5 and occludin in HUVECs, and upregulates the expression of antioxidant factors NRF2 and HO-1^[3]. In Vivo:Alvelestat (AZD9668) (10 mg/kg; p.o.; daily; from the day of irradiation to euthanasia) reduces radiation-induced NET formation, restores endothelial tight junction integrity, decreases vascular leakage, suppresses inflammatory responses, and accelerates wound healing in a mouse model of radiation-induced skin injury^[3].
Alvelestat (0.1-5 mg/kg; p.o.) significantly attenuates pulmonary hemorrhage induced by human neutrophil elastase (NE) in female C57BL/6JBomTac mice^[4].
Alvelestat (2.5-20 mg/kg; p.o.) significantly reduces collagen degradation induced by human neutrophil elastase (NE) in female HanTac: WH rats; at doses of 10 mg/kg and above, it reduces elastin degradation^[4].
Alvelestat (1-10 mg/kg; p.o.; twice daily for 4 consecutive days) reduces smoke-induced BAL neutrophil counts in female BALB/cJBomTac mice, and decreases IL-1β levels in BAL at doses ≥1 mg/kg^[4].
Alvelestat (100 mg/kg; p.o.; once daily) completely inhibits smoke-induced pulmonary inflammation, emphysema and small airway remodeling in female Hartley guinea pigs^[4].