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Purity: ≥98%
BAY-678 racemate is a racemate of BAY-678 which 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.
| Targets |
BAY-678 while maintaining outstanding target selectivity, picomolar potency was achieved by locking the bioactive conformation of these inhibitors with a strategically positioned methyl sulfone substituent. An induced-fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE.[1]
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| ln Vitro |
BAY-678 while maintaining outstanding target selectivity, picomolar potency was achieved by locking the bioactive conformation of these inhibitors with a strategically positioned methyl sulfone substituent. An induced-fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE.[1]
BAY-678 is a potent and selective inhibitor of human neutrophil elastase (HNE), with an IC₅₀ of 20 nM and a Kᵢ of 15 nM. It demonstrates high species selectivity, showing much weaker inhibition against rodent orthologous enzymes (RNE Kᵢ: 600 nM; MNE Kᵢ: 700 nM). The compound exhibited no inhibitory activity against 21 related serine proteases at concentrations up to 30 µM. [1] BAY-678 was selected as a chemical probe candidate for HNE due to its balanced profile regarding polarity and potency. [1] The compound belongs to the 1,4-dihydropyrimidinone class and showed an overall decreased inhibitory potency against CYP isoforms compared to earlier lead structures. For example, amide 23 (a close analogue) elicited no observable inhibition toward CYP2C9 and CYP3A4 up to 50 µM. [1] |
| Enzyme Assay |
To confirm the exceptionally high potency of BAY-678 and BAY 85-8501 , we measured enzyme reaction velocities with different substrate concentrations at various inhibitor concentrations and extrapolated the inhibition constants (Ki) from Dixon plots. Both compounds revealed (substrate) competitive inhibition, further confirming their binding into the active site of the enzyme. However, the Ki values toward rodent orthologous enzymes were about two orders of magnitude higher than toward HNE. Beneficially, BAY-678 and BAY 85-8501 revealed no inhibition against 21 related serine proteases, up to an inhibitor concentration of 30 μm .[1]
The inhibitory capacity of test compounds against HNE was assessed using functional biochemical assays with the isolated enzyme. Enzyme activity was measured at pH 7.4 in the presence or absence of various compound concentrations using a suitable fluorogenic peptide substrate, MeOSuc-AAPV-AMC. IC₅₀ values were derived from these activity data. [1] For the determination of inhibition constants (Kᵢ), enzyme reaction velocities were measured with different substrate concentrations at various inhibitor concentrations. The Kᵢ values were then extrapolated from Dixon plots, confirming competitive inhibition for compounds like BAY-678 and BAY 85-8501. [1] The capacity of test compounds to inhibit human CYP2C9 and CYP3A4 was investigated using pooled human liver microsomes as the enzyme source and selective standard substrates (diclofenac for CYP2C9 and midazolam for CYP3A4). IC₅₀ values were derived from enzyme activity data (pH 7.4) in the presence or absence of various compound concentrations. [1] Metabolic stability was assessed in the presence of rat hepatocytes by determining the half-life of the compound. Clearance parameters and estimated maximum oral bioavailability (Fmax) values were calculated from this half-life. [1] |
| ADME/Pharmacokinetics |
Pharmacokinetic studies of several dihydropyrimidinones, including BAY-678 (compound 20), were conducted in rats. Drugs prepared in ethanol/polyethylene glycol 400/water were administered intravenously (0.25–2 hours infusion) and orally (gavage) at doses of 0.3 mg kg⁻¹, and mean values were determined. For BAY-678: Total plasma clearance (CL) was 2.0 L h⁻¹ kg⁻¹. Apparent steady-state volume of distribution (Vss) was 3.9 L kg⁻¹. Half-life (t₁/₂) was 1.3 hours. Oral bioavailability (F) was 83%. [1]
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| References | |
| Additional Infomation |
In the process of optimizing the series of dihydropyrimidinone lead compounds, BAY-678 (20) was identified as a chemical probe candidate for human neutrophil elastase (HNE). Its discovery is part of a strategy to develop selective and potent HNE inhibitors for the treatment of lung diseases. [1]
This paper details the structure-activity relationship (SAR) studies from the initial screening of lead compounds to highly effective inhibitors such as BAY-678 and finally BAY 85-8501. A key strategy was to “freeze the bioactive conformation” by introducing substituents such as the methyl group at the N3 position, thereby locking the dihedral angle of the north-side phenyl substituent and thus improving binding efficiency and potency. [1] BAY-678 itself has not yet entered clinical trials; the clinical candidate derived from this series is BAY 85-8501. [1] |
| Molecular Formula |
C20H15F3N4O2
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| Molecular Weight |
400.353914499283
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| Exact Mass |
400.114
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| CAS # |
675103-35-2
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| Related CAS # |
BAY-677;2117404-84-7;BAY-678;675103-36-3
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| PubChem CID |
59218311
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
2.5
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
29
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| Complexity |
755
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1(C#N)=NC=C(C2C(C(C)=O)=C(C)N(C3=CC=CC(C(F)(F)F)=C3)C(=O)N2)C=C1
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| InChi Key |
PGIVGIFOWOVINL-GOSISDBHSA-N
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| 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
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| Chemical Name |
(R)-5-(5-acetyl-6-methyl-2-oxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-4-yl)picolinonitrile
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| Synonyms |
BAY-678 racemate; BAY678 racemate; BAY 678 racemate.
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO : ≥ 150 mg/mL (~374.67 mM)
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| 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) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: 2.5 mg/mL (6.24 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Selection of HNE inhibitors that have reached clinical development.ChemMedChem. 2015 Jul;10(7):1163-73. |
Locking the bioactive conformation with substituents at N3 and C2′. Conformational analysis of free ligands based on modeling. Relaxed coordinate scan of the rotation of the cyanophenyl moiety of 22 and 27 from 0° to 180° in steps of 2°. Depicted is the dihedral angle along N3=C4=C1′=C2′.ChemMedChem. 2015 Jul;10(7):1163-73. |
Induced-fit binding mode. Protease (HNE) residues are shown in stick representation (white) with transparent Connolly-like surface.[], [] Ligand 19 (purple) is shown in ball-and-stick model (oxygen: red, nitrogen: blue, fluorine: cyan); hydrogen bonds are depicted as broken yellow lines. a) Structure of HNE in complex with 19. Ligand 19 interacts with HNE by a hydrogen bond (3.1 Å) formed between the C2 carbonyl oxygen atom of the central pyrimidine ring and the Val216 backbone amide of HNE.ChemMedChem. 2015 Jul;10(7):1163-73. |
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