ZD-0892
目录号 : GC32628ZD-0892是选择性和有效的中性粒细胞弹性蛋白酶(neutrophilelastase)抑制剂,对于人嗜中性粒细胞弹性蛋白酶和猪胰弹性蛋白酶的Ki值分别为6.7和200nM。
Cas No.:171964-73-1
Sample solution is provided at 25 µL, 10mM.
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Animal experiment: | Rats[2]Adult male Sprague-Dawley rats (250-300 g in body weight) are induced pulmonary hypertension. In addition to a group of untreated rats, the experimental groups include rats that receive twice-daily gavage tube feedings of ZD0892, at a dose of 240 mg/kg per day or vehicle (5% polyethylene glycol or dimethyl sulfoxide). Rats are examined after 7 days of treatment.Mice[1]DBA/2 male mice 8 weeks old is used. ZD0892 is given in a dose of 60 mg/kg or 120 mg/kg[1]. |
References: [1]. Lee JK, et al. A serine elastase inhibitor reduces inflammation and fibrosis and preserves cardiac function after experimentally-induced murine myocarditis. Nat Med. 1998 Dec;4(12):1383-91. |
ZD-0892 is a selective and potent inhibitor of a neutrophil elastase with Kis of 6.7 and 200 nM for human neutrophil elastase and porcine pancreatic elastase, respectively.
ZD0892 administration to DBA/2 mice infected with the EMC virus results in reduced myocardial elastolytic activity and coronary microvascular perfusion injury. ZD0892 decreases the pathologic severity of the myocardial lesions associated with murine viral myocarditis[1]. ZD-0892 can reverse advanced pulmonary vascular disease produced in rats[2].
[1]. Lee JK, et al. A serine elastase inhibitor reduces inflammation and fibrosis and preserves cardiac function after experimentally-induced murine myocarditis. Nat Med. 1998 Dec;4(12):1383-91. [2]. Cowan KN, et al. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med. 2000 Jun;6(6):698-702.
Cas No. | 171964-73-1 | SDF | |
Canonical SMILES | CC(C)[C@@H](C(N1[C@H](C(N[C@H](C(C(F)(F)F)=O)C(C)C)=O)CCC1)=O)NC(C2=CC=C(OC)C=C2)=O | ||
分子式 | C24H32F3N3O5 | 分子量 | 499.52 |
溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
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1 mM | 2.0019 mL | 10.0096 mL | 20.0192 mL |
5 mM | 0.4004 mL | 2.0019 mL | 4.0038 mL |
10 mM | 0.2002 mL | 1.001 mL | 2.0019 mL |
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ZD-0892 AstraZeneca
Curr Opin Investig Drugs 2000 Oct;1(2):227-9.PMID:11249578doi
ZD-0892, a neutrophil elastase inhibitor, is under development by AstraZeneca as a potential treatment for chronic obstructive pulmonary disease (COPD) and peripheral vascular disease (PVD). It is in phase I clinical trials for these two indications [315489]. The compound was originally under investigation for the potential treatment of asthma, but development was discontinued for this indication [266604]. The compound is the follow-up to ZD-8321 (qv) [336599].
[Effect of elastase inhibitor on pulmonary hypertension induced by monocrotaline]
Zhonghua Er Ke Za Zhi 2004 May;42(5):375-8.PMID:15189699doi
Objective: Pulmonary hypertension is a proliferative vascular disease characterized by pulmonary vascular structural remodeling. Until now, the pathogenesis of pulmonary hypertension is still not fully understood. Although considerable progress has been made, there is, to date, no cure for advanced pulmonary vascular disease. Recently, a number of studies suggest that endogenous vascular elastase (EVE) play a role in the vascular changes associated with pulmonary hypertension. The purpose of the study was to determine whether an elastase inhibitor might reverse advanced pulmonary vascular disease produced in rats by injection of monocrotaline. Methods: One hundred and twenty male Sprague-Dawley rats were used in this study. The rats were divided into three groups: control, model and ZD-0892 groups. In the model and ZD-0892 groups, the rats were subjected to a single subcutaneous injection of monocrotaline (60 mg/kg) in the hind flank, while the rats in control group received an equivalent volume of 0.9% saline. From day 21, the rats in the ZD-0892 and model groups received twice-daily gavage tube feedings of either ZD-0892 at a dose of 240 mg/kg per day or its administration vehicle, while the rats in control group were subjected to an equivalent volume of 0.9% saline. On days 21, 28 and 35 post-injection, the elastolytic activity was measured with a fluorescence microplate reader and pulmonary artery pressure was detected via catheterization. Meanwhile, the lungs were evaluated morphologically, using the barium-gelatin perfusion technique. Results: The injection of monocrotaline led to severe pulmonary hypertension in rats 21 days later and pulmonary artery elastolytic activity increased remarkably. A 1-week treatment with ZD-0892 resulted in declines in elastase activity. This was associated with significant declines in pulmonary artery pressure, decreases in muscularization of peripheral arteries and reductions in medial hypertrophy. After 2 weeks, elastase activity returned to normal level. Pulmonary artery pressure and structure were normalized. Conclusion: Increased elastase activity is important in the development of vascular changes and progressive pulmonary hypertension. ZD-0892 can suppress the elastase activity and completely reverse the fatal pulmonary hypertension induced by monocrotaline in rats.
Neutrophil elastase inhibitors as treatment for COPD
Expert Opin Investig Drugs 2002 Jul;11(7):965-80.PMID:12084007DOI:10.1517/13543784.11.7.965.
Chronic obstructive pulmonary disease, characterised by a slowly progressive, irreversible airways limitation, is a major worldwide cause of chronic morbidity and mortality. The imbalance between human neutrophil elastase and endogenous antiproteases may cause excess human neutrophil elastase in pulmonary tissues, which may be considered a major pathogenic factor in chronic obstructive pulmonary disease. Great effort has been devoted to finding a method to restore the balance, resulting in the discovery of potent two-typed small-molecular-weight human neutrophil elastase inhibitors. In the application of chronic obstructive pulmonary disease therapy, the human neutrophil elastase inhibitors mainly focused upon include ONO-5046, MR-889, L-694,458, CE-1037, GW-311616 and TEI-8362 as the acyl-enzyme inhibitors; and ONO-6818, AE-3763, FK-706, ICI-200,880, ZD-0892 and ZD-8321 as the transition-state inhibitors. In this review, various problems that remain to be solved in the clinical use of human neutrophil elastase inhibitors are discussed.