BAY-678 is a novel, potent, orally bioavailable, selective and cell-permeable inhibitor of human neutrophil elastase (HNE) with an IC50 of 20 nM. Human neutrophil elastase (HNE) is a key protease for matrix degradation. High HNE activity is observed in inflammatory diseases. Accordingly, HNE is a potential target for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), bronchiectasis (BE), and pulmonary hypertension (PH). HNE inhibitors should reestablish the protease-anti-protease balance. BAY-678 is also nominated as a chemical probe to the public via the Structural Genomics Consortium (SGC). BAY-678 has a favorable pharmacokinetic profile. The cell based activity of BAY-678 on HNE is not relevant and has not been measured. Efficacy was demonstrated in acute in vivo models, for example, protease-induced acute lung injury (ALI) in mice, where exogenous HNE in the mouse lung was inhibited with Ki = 15 nM after oral administration.
Physicochemical Properties
| Molecular Formula | C20H15F3N4O2 |
| Molecular Weight | 400.353914499283 |
| Exact Mass | 400.114 |
| CAS # | 675103-36-3 |
| Related CAS # | BAY-677;2117404-84-7;BAY-678 racemate;675103-35-2 |
| PubChem CID | 23728722 |
| Appearance | Light yellow to yellow solid powder |
| LogP | 2.5 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 3 |
| Heavy Atom Count | 29 |
| Complexity | 755 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | CC1=C([C@@H](C2=CN=C(C#N)C=C2)NC(=O)N1C1C=CC=C(C(F)(F)F)C=1)C(=O)C |
| InChi Key | PGIVGIFOWOVINL-GOSISDBHSA-N |
| InChi Code | InChI=1S/C20H15F3N4O2/c1-11-17(12(2)28)18(13-6-7-15(9-24)25-10-13)26-19(29)27(11)16-5-3-4-14(8-16)20(21,22)23/h3-8,10,18H,1-2H3,(H,26,29)/t18-/m1/s1 |
| Chemical Name | 5-[(6R)-5-acetyl-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-1,6-dihydropyrimidin-6-yl]pyridine-2-carbonitrile |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | With an IC50 of 20 nM, BAY-678 is a powerful, selective, cell-permeable, and orally accessible inhibitor of human neutrophil elastase (HNE). For MNE, BAY-678 has a Ki value of 700 nM. A fourth-generation HNE inhibitor is BAY-678 [1]. Through the Structural Genomics Consortium (SGC), BAY-678 has also been proposed to the general public as a chemical probe [2]. A panel of 21 serine proteases is more than 2,000 times more selectively inhibited by BAY-678 [3]. |
| ln Vivo | In preclinical models of ALI and emphysema, BAY-678 (17) demonstrated notable effectiveness, indicating its anti-inflammatory and anti-remodeling mechanism of action. Additionally, in rat and mouse models of PAH, BAY-678 (17) demonstrated noteworthy positive effects on pulmonary hemodynamics and vascular effects [2]. |
| References |
[1]. 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. [2]. Neutrophil elastase inhibitors for the treatment of (cardio)pulmonary diseases: Into clinical testing with pre-adaptive pharmacophores. Bioorg Med Chem Lett. 2015 Oct 15;25(20):4370-81. [3]. BAY-678 Selective chemical probe for Human Neutrophil Elastase. |
Solubility Data
| Solubility (In Vitro) |
DMSO : ≥ 100 mg/mL (~249.78 mM) Ethanol :≥ 4.76 mg/mL (~11.89 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.24 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.24 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4978 mL | 12.4891 mL | 24.9781 mL | |
| 5 mM | 0.4996 mL | 2.4978 mL | 4.9956 mL | |
| 10 mM | 0.2498 mL | 1.2489 mL | 2.4978 mL |