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BAY-85-8501

Names

[ CAS No. ]:
1161921-82-9

[ Name ]:
BAY-85-8501

[Synonym ]:
(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarbonitrile
5-Pyrimidinecarbonitrile, 4-[4-cyano-2-(methylsulfonyl)phenyl]-1,2,3,4-tetrahydro-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-, (4S)-

Biological Activity

[Description]:

BAY-85-8501 is a selective and potent inhibitor of Human Neutrophil Elastase (HNE), with an IC50 of 65 pM.

[Related Catalog]:

Signaling Pathways >> Metabolic Enzyme/Protease >> Elastase
Research Areas >> Metabolic Disease

[Target]

IC50: 65 pM (HNE)[1].


[In Vivo]

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].

[Animal admin]

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].

[References]

[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.


[Related Small Molecules]

DMP 777 | GW311616 | Sivelestat Sodium tetrahydrate | Alvelestat | AE-3763 | BAY 678 | Lodelaben | ZD-0892 | ZD8321

Chemical & Physical Properties

[ Density]:
1.5±0.1 g/cm3

[ Boiling Point ]:
626.7±55.0 °C at 760 mmHg

[ Molecular Formula ]:
C22H17F3N4O3S

[ Molecular Weight ]:
474.456

[ Flash Point ]:
332.8±31.5 °C

[ Exact Mass ]:
474.097351

[ LogP ]:
1.99

[ Vapour Pressure ]:
0.0±1.8 mmHg at 25°C

[ Index of Refraction ]:
1.622

Related Compounds