FK706
目录号 : GC61744
FK706是一种有效，缓慢结合和竞争性的人中性粒细胞弹性蛋白酶抑制剂，IC50为83nM，Ki为4.2nM。FK706还抑制小鼠中性粒细胞弹性蛋白酶和猪胰弹性蛋白酶，IC50分别为22nM和100nM，并且对其他丝氨酸蛋白酶(例如人胰胰蛋白酶，人胰腺α-胰凝乳蛋白酶和人白细胞组织蛋白酶G)没有抑制活性。FK706具有抗炎作用。
Cas No.:144055-55-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.50%
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- Datasheet
FK706 is a potent, slow-binding and competitive inhibitor of human neutrophil elastase with an IC50 of 83 nM and a Ki of 4.2 nM. FK706 also inhibits mouse neutrophil elastase and porcine pancreatic elastase with IC50s of 22 nM and 100 nM, respectively, and has no inhibitory activity against other serine proteinases such as human pancreatic trypsin, human pancreatic α-chymotrypsin and human leukocyte cathepsin G. FK706 has anti-inflammatory effect[1][2].
FK706 effectively inhibits the hydrolysis of bovine neck ligament elastin (2 mg/mL final concentration) by human neutrophil elastase (4 μg/mL final concentration) with an IC50 value of 230 nM[1]. FK706 blocks the release of inflammatory chemokines, suppresses the expression of IL-8 and MCP-1 mRNA, and suppresses NF-κB activation. It seems possible that FK706 may directly blocks human lung fibroblasts activation of NF-κB, preventing expression of inflammatory chemokines during cigarette smoke-induced lung inflammation[2].
FK706 (10-100 mg/kg; subcutaneous injection; for 1-6 hours; male C57BL mice) treatment significantly suppresses human neutrophil elastase (20 μg/paw)-induced paw edema in mice in a dose-dependent manner (47% inhibition at a dose of 100 mg/kg)[1]. Animal Model: Male C57BL mice (6 weeks old) injected with human neutrophil elastase[1]
[1]. Shinguh Y, et al. Biochemical and pharmacological characterization of FK706, a novel elastase inhibitor. Eur J Pharmacol. 1997 Oct 15;337(1):63-71. [2]. Numanami H, et al. Serine protease inhibitors modulate smoke-induced chemokine release from human lung fibroblasts. Am J Respir Cell Mol Biol. 2003 Nov;29(5):613-9.
| Cas No. | 144055-55-0 | SDF | |
| Canonical SMILES | O=C(NC(C(C)C)C(C(F)(F)F)=O)[C@H]1N(C([C@H](C(C)C)NC(C2=CC=C(C(NCC(O[Na])=O)=O)C=C2)=O)=O)CCC1 | ||
| 分子式 | C26H32F3N4NaO7 | 分子量 | 592.54 |
| 溶解度 | DMSO: 115 mg/mL (194.08 mM) | 储存条件 | 4°C, protect from light |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.6876 mL | 8.4382 mL | 16.8765 mL |
| 5 mM | 0.3375 mL | 1.6876 mL | 3.3753 mL |
| 10 mM | 0.1688 mL | 0.8438 mL | 1.6876 mL |
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2.
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Biochemical and pharmacological characterization of FK706, a novel elastase inhibitor
Eur J Pharmacol 1997 Oct 15;337(1):63-71.PMID:9389382DOI:10.1016/s0014-2999(97)01284-3.
FK706, sodium 2-[4-[[(S)-1-[[(S)-2-[[(RS)-3, 3, 3-trifluoro-1-isopropyl-2-oxopropyl]aminocarbonyl]pyrrolidin -1-yl]carbonyl]-2-methylpropyl] aminocarbonyl] benzoylamino] acetate, C26H32F3N4NaO7, is a synthetic water-soluble inhibitor of human neutrophil elastase. This compound demonstrated a competitive and slow-binding inhibition of human neutrophil elastase with a Ki of 4.2 nM. In studies using synthetic substrates, FK706 inhibited human neutrophil elastase activity and porcine pancreatic elastase activity with respective IC50 values of 83 and 100 nM. FK706, however, inhibited more weakly, (IC50 values > 340 microM) other serine proteinases such as human pancreatic alpha-chymotrypsin, human pancreatic trypsin and human leukocyte cathepsin G. FK706 also effectively inhibited the hydrolysis of bovine neck ligament elastin (2 mg/ml final concentration) by human neutrophil elastase (4 microg/ml final concentration) with an IC50 value of 230 nM. FK706 protected animals against human neutrophil elastase (50 microg/animal)-induced lung hemorrhage with ED50 values of 2.4 microg/animal by intratracheal administration and 36.5 mg/kg by intravenous administration, respectively. Subcutaneous administration of FK706 significantly suppressed human neutrophil elastase (20 microg/paw)-induced paw edema in mice in a dose-dependent manner (47% inhibition at a dose of 100 mg/kg). These results suggest that FK706 would be a useful tool for investigating the role of human neutrophil elastase in inflammatory disorders associated with an excess of elastase, such as pulmonary emphysema, adult respiratory distress syndrome, septic shock, cystic fibrosis, chronic bronchitis and rheumatoid arthritis.
Smoking accelerates absorption of inhaled neutrophil elastase inhibitor FK706
Clin Pharmacol Ther 1999 Nov;66(5):501-8.PMID:10579477DOI:10.1016/S0009-9236(99)70013-5.
Purpose: We compared the pharmacokinetics of the inhaled novel neutrophil elastase inhibitor FK706 between healthy nonsmokers and smokers. Methods: Six healthy nonsmokers and six smokers inhaled 50 to 400 mg FK706 in two different doses. Series of plasma concentrations of the SSS form of FK706 (pharmacologically active epimer) were analyzed model dependently and independently. Pharmacokinetic parameters obtained from each group were compared after standardization by doses. Results: The plasma concentration-time curve of inhaled FK706 was apparently different between smokers and nonsmokers. The maximum plasma concentrations (Cmax) were significantly higher in the smokers than in the nonsmokers (smokers, 1.47 +/- 0.62 ng/mL/mg; nonsmokers, 0.49 +/- 0.14 ng/mL/mg [mean +/- SD; P < .01]). The time to reach Cmax (tmax) and elimination half-life (t1/2) were statistically smaller in the smokers compared with the tmax and elimination t1/2 in the nonsmokers (tmax in smokers, 0.44 +/- 0.27 hours; tmax in nonsmokers, 1.17 +/- 0.39 hours [P < .01]; t1/2 in smokers, 1.23 +/- 0.40 hours; t1/2 in nonsmokers, 2.73 +/- 0.57 hours [P < .01]). The area under the plasma concentration-time curve and plasma clearance were not significantly different between the two groups. Model-dependent pharmacokinetic analysis, assuming a flip-flop model, revealed that the absorption rate constant (ka) was about 10 times greater in smokers than the ka in nonsmokers. Conclusion: Significant increases of Cmax and ka and reductions of tmax and elimination t1/2 of the inhaled FK706 were observed in the healthy smokers, suggesting that the smoking habit accelerates the drug absorption after inhalation. These results suggest that we should pay attention to the drug-related adverse events caused by smoking, especially when the drug has a narrow therapeutic range.
Serine protease inhibitors modulate smoke-induced chemokine release from human lung fibroblasts
Am J Respir Cell Mol Biol 2003 Nov;29(5):613-9.PMID:12738688DOI:10.1165/rcmb.2003-0113OC.
Smoking is associated with lung inflammation and a protease-antiprotease imbalance. We previously reported that cigarette smoke extract (CSE) stimulates human lung fibroblasts to release chemotactic cytokines. We hypothesized that serine protease inhibitors might modulate lung fibroblast release of chemotactic cytokines in response to CSE. To test this hypothesis, serine protease inhibitors (FK706, alpha1-antitrypsin, methoxysuccinyl-Ala-Ala-Pro-Val chloromethyl ketone, or Nalpha-p-tosyl-L-lysine chloromethyl ketone) were evaluated for their capacity to attenuate the release of neutrophil chemotactic activity (NCA) and monocyte chemotactic activity (MCA) from human fetal lung fibroblasts by the blind-well chemotactic chamber. Metalloproteinases and cysteine proteinases were not examined in this study. Similarly, the release and gene expression of chemokines and nuclear factor-kappaB (NF-kappaB) activation were measured by means of enzyme-linked immunosorbent assay and reverse transcriptase-polymerase chain reaction. Release of NCA, MCA, chemotactic chemokines including interleukin-8, granulocyte colony-stimulating factor, monocyte chemoattractant protein-1, and granulocyte-macrophage colony-stimulating factor, and the expression of interleukin-8 and monocyte chemoattractant protein-1 mRNA were attenuated by FK706. Furthermore, FK706 suppressed NF-kappaB activation. These data suggest that serine protease inhibitors attenuate the CSE-induced release of NCA and MCA from human fetal lung fibroblasts and that the inhibitory action of antiproteases might depend on NF-kappaB signaling pathway.
Neutrophil elastase inhibitor attenuates lipopolysaccharide-induced hepatic microvascular dysfunction in mice
Shock 2002 Aug;18(2):163-8.PMID:12166781DOI:10.1097/00024382-200208000-00013.
The present study was conducted to elucidate the role of neutrophil elastase in lipopolysaccharide (LPS)-induced hepatic microvascular injury by using in vivo microscopy. The intravenous (i.v.) injection of LPS (0.1 mg/kg) in male C3H/HeN mice caused significant hepatic microcirculatory dysfunction: leukocyte adhesion to the sinusoids as well as to the venule, and reduced sinusoidal perfusion, in comparison with vehicle-treated mice. Concomitantly, the serum alanine aminotransferase (ALT) activity at 4 h after LPS injection was significantly increased. The serum concentrations of tumor necrosis factor (TNFalpha) and interleukin-1beta (IL-1beta) at 1 h and at 4 h after LPS injection, respectively, were significantly elevated. Neutrophil elastase inhibitors, ONO-5046 (30 and 90 mg/kg, i.v., 0 and 2 h after LPS injection) or FK706 (30 and 100 mg/kg, i.v., 0 and 2 h after LPS injection) minimized the LPS-induced hepatic microcirculatory dysfunction in a dose-dependent manner. Treatment with ONO-5046 and FK706 significantly reduced the ALT level as well as the serum concentrations of TNFalpha and IL-1beta. In addition, ONO-5046 and FK706 attenuated both hepatic microcirculatory dysfunction and liver injury mediated by TNFalpha and IL-1beta (10 microg/kg i.v.). Furthermore, both ONO-5046 and FK706 improved human neutrophil elastase (10 microg/kg i.v.)-induced hepatic microcirculatory dysfunction, although neutrophil elastase did not increase the levels of TNFalpha and IL-1beta. These results suggest that neutrophil elastase aggravates the LPS-induced hepatic microvascular dysfunction. Neutrophil elastase inhibitors attenuate hepatic microvascular dysfunction in response to LPS by inhibiting TNFalpha and IL-1beta production. Neutrophil elastase inhibitors also reduce the microvascular dysfunction mediated by TNFalpha and IL-1beta as well as by neutrophil elastase.