ZD8321
目录号 : GC32005ZD8321是人Neutrophilelastase(NE)的有效抑制剂,其Ki值为13±1.7nM。
Cas No.:182073-77-4
Sample solution is provided at 25 µL, 10mM.
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Cell experiment: | HUVECs are cultured in RPMI 1640 containing 5% FBS for 6 h in collagen-coated, 24-well plates before the experiment. Some of the confluent HUVECs are further incubated with TNFα (1 ng/mL) and ZD8321 (0-50 mM), or with human NE (0-100ng/mL) for 4 h at 37°C. For adhesion assays, cancer cells resuspended in RPMI 1640 containing 5% FBS are added to each HUVEC-layered well. The plates are shaken at 700 rpm for 10 min at room temperature, washed twice with PBS, and examined by phase-contrast microscopy to determine the number of cells bound onto the HUVEC monolayer. The adhesive reactions of neutrophils to HUVEC are also analyzed in this manner[2]. |
References: [1]. Veale CA, et al. Orally active trifluoromethyl ketone inhibitors of human leukocyte elastase. J Med Chem. 1997 Sep 26;40(20):3173-81. |
ZD8321 is a potent inhibitor of human Neutrophil elastase (NE) with a Ki of 13±1.7 nM.
TNFα-activated HUVEC is dose dependently inhibited by ZD8321.The adhesion between cancer cells with high elastase activity and TNFα-activated HUVEC is also inhibited by ZD8321. Expression of cell surface E-selectin by NE stimulation is suppressed in the presence of ZD8321. The concentration of soluble E-selectin in the medium increases after adhesive reaction between neutrophils and HUVEC. This increase is also dose dependently inhibited by ZD8321[2].
[1]. Veale CA, et al. Orally active trifluoromethyl ketone inhibitors of human leukocyte elastase. J Med Chem. 1997 Sep 26;40(20):3173-81. [2]. Nozawa F, et al. Elastase activity enhances the adhesion of neutrophil and cancer cells to vascular endothelial cells. J Surg Res. 2000 Dec;94(2):153-8.
Cas No. | 182073-77-4 | SDF | |
Canonical SMILES | COC(N[C@@H](C(C)C)C(N1[C@@H](CCC1)C(N[C@@H](C(C)C)C(C(F)(F)F)=O)=O)=O)=O | ||
分子式 | C18H28F3N3O5 | 分子量 | 423.43 |
溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.3617 mL | 11.8083 mL | 23.6167 mL |
5 mM | 0.4723 mL | 2.3617 mL | 4.7233 mL |
10 mM | 0.2362 mL | 1.1808 mL | 2.3617 mL |
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Orally active trifluoromethyl ketone inhibitors of human leukocyte elastase
This paper describes the development a series of peptidyl trifluoromethyl ketone inhibitors of human leukocyte elastase which are found to have excellent pharmacological profiles. Methods have been developed that allow for the synthesis of these inhibitors in stereochemically pure form. Two of these compounds, 1k and 1l, have high levels of oral bioavailability in several species. Compound 1l has entered development as ZD8321 and is presently undergoing clinical evaluation. These compounds demonstrate that peptidyl trifluoromethyl ketone inhibitors can achieve high levels of oral activity and bioavailability, and therefore they may prove useful as therapeutic agents in the treatment of diseases in which elastase is implicated.
Elastase activity enhances the adhesion of neutrophil and cancer cells to vascular endothelial cells
Background: Elastase activity in cancer cells has been reported to promote their metastasis. Hence, we analyzed the influence of elastase activity of cancer cells on their responsive adhesion to vascular endothelial cells.
Materials and methods: Human pancreatic (S2-007, S2-013, S2-020, S2-028) and colonic (COLO205) cancer cell lines were used. S2-007, S2-013, and S2-020 possess high elastase activity, whereas S2-028 and COLO205 have low elastase activity. Adhesive reactions of these cancer cells and neutrophils to TNFalpha-activated HUVEC were analyzed. Bound cells onto HUVEC were counted after incubation for 10 min. The effects of suppression of elastase activity by ZD8321, a potent elastase inhibitor, and supplementation of human neutrophil elastase (NE) on the adhesive reactions were also analyzed. In addition, E-selectin expression on HUVEC and concentrations of soluble E-selectin in the medium were measured.
Results: Adhesion of cells with high intracellular elastase activity to TNFalpha-activated HUVEC was suppressed by ZD8321. On the other hand, adhesion of cells with low elastase activity was enhanced by exogenous NE. Expression of E-selectin, a key molecule in leukocyte-endothelial cell interaction, on HUVEC was increased by NE. Soluble E-selectin concentration in the medium increased after the adhesive reaction between neutrophils and HUVEC. This increase was thought to be due to the shedding of cell surface E-selectin. Such responses were inhibited by ZD8321.
Conclusion: Elastase activity has a biological function of stimulating both the E-selectin expression on HUVEC and the resultant adhesive reaction of cancer cells with them. Inhibition of elastase activity is a potent strategy for controlling cancer metastasis.
Neutrophil elastase inhibitors as treatment for COPD
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.
ZD-0892 AstraZeneca
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].