BAY-85-8501是人类中性脂酶(HNE)的一个有效的、选择性抑制剂，其IC50值为65pM。
BAY-85-8501 is a selective and potent inhibitor of Human Neutrophil Elastase (HNE), with an IC50 of 65 pM.
In this model the exogenous HNE noxa is the primary cause of injury and lung hemorrhage. Based on picomolar potency against HNE as well as single digit potency versus MNE, BAY-85-8501 (29) completely prevents the development of lung injury and subsequent inflammation when administered 1 h prior to the HNE noxa. In the 0.01 mg/kg dose group, hemoglobin concentration is already significantly decreased. At a dose of 0.1 mg/kg, a significant effect on neutrophil count is observed. In this setup, efficacy is predominantly driven by potency against HNE (Ki=0.08 nM). As the highly HNE-selective inhibitor BAY 85-8501 has no effect on PPE, BAY-85-8501 could not prevent the primary lung injury in this setup. Nevertheless, BAY-85-8501 could inhibit MNE, the endogenous driver of inflammation and secondary injury, although with decreased potency. Consequently, the effects of BAY-85-8501 on inflammation and secondary injury are weaker at this point, and only observed at 30-fold higher doses. Efficacy is predominantly driven by potency against MNE (Ki=6 nM) in this second setup[1].
[1]. Von Nussbaum F, et al. Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases. ChemMedChem. 2015 Jul;10(7):1163-73.
Animal experiment: | Mice[1]Elastaseinduced lung failure in mice, rats or hamsters is a widely used animal model of acute lung failure. The animals are treated 1 hour prior to orotracheal instillation of human neutrophil elastase (HNE) or porcine pancreatic elastase (PPE). In this study, each mouse receives BAY-85-8501 with different concentrations (0.003, 0.01, 0.03, 0.1, 0.3, 3, 10, 30 mg/kg) by P.O.[1]. |
参考文献: [1]. Von Nussbaum F, et al. Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases. ChemMedChem. 2015 Jul;10(7):1163-73. | |
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