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Purity: ≥98%
BAY 85-8501 is a novel, highly potent and selective inhibitor of Human Neutrophil Elastase (HNE) with an IC50 of 65 pM. BAY 85-8501 exhibited high in vivo efficacy in various preclinical animal models and is currently being studied in clinical studies for the treatment of pulmonary diseases. 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. By means of medicinal chemistry a novel dihydropyrimidinone lead-structure class was identified. Further chemical optimization yielded orally active compounds with favorable pharmacokinetics such as the chemical probe 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. BAY 85-8501 ((4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) was shown to be efficacious in a rodent animal model related to ALI. BAY 85-8501 is currently being tested in clinical studies for the treatment of pulmonary diseases.
| ln Vivo |
In this scenario, the main source of damage and pulmonary bleeding is exogenous HNE noxa. When provided one hour before to HNE noxa, BAY-85-8501 (29) entirely avoided the development of lung damage and subsequent inflammation, based on picomolar potency against HNE and single-digit potency against MNE. There has been a substantial decrease in hemoglobin concentration in the 0.01 mg/kg dosage group. There was a noticeable impact on neutrophil counts at 0.1 mg/kg. In this situation, potency against HNE (Ki=0.08 nM) was the main factor influencing efficacy. In this context, BAY-85-8501, a highly HNE-selective inhibitor, does not prevent primary lung injury since it has no effect on PPE. Though less potently, BAY-85-8501 can block MNE, an endogenous driver of inflammation and secondary damage. As a result, BAY-85-8501 now has a minimal impact on inflammation and secondary damage and is only noticeable at doses that are thirty times higher. Potency against MNE (Ki=6 nM) is the primary factor influencing efficacy in the second setting [1].
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| 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
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| Molecular Formula |
C22H17F3N4O3S
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|---|---|
| Molecular Weight |
474.455593824387
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| CAS # |
1161921-82-9
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| Related CAS # |
(R)-BAY-85-8501;2446175-39-7
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| SMILES |
N#CC1=C(C)N(C2=CC=CC(C(F)(F)F)=C2)C(N(C)[C@@H]1C3=CC=C(C#N)C=C3S(=O)(C)=O)=O
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| InChi Key |
YAJWYFPMASPAMM-HXUWFJFHSA-N
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| InChi Code |
InChI=1S/C22H17F3N4O3S/c1-13-18(12-27)20(17-8-7-14(11-26)9-19(17)33(3,31)32)28(2)21(30)29(13)16-6-4-5-15(10-16)22(23,24)25/h4-10,20H,1-3H3/t20-/m1/s1
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| Chemical Name |
(S)-4-(4-cyano-2-(methylsulfonyl)phenyl)-3,6-dimethyl-2-oxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
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| Synonyms |
BAY 858501; BAY858501; BAY-858501; BAY 85-8501; BAY85-8501; BAY-85-8501.
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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 : ~200 mg/mL (~421.53 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (10.54 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 50.0 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: ≥ 5 mg/mL (10.54 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 50.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 2.5 mg/mL (5.27 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1077 mL | 10.5383 mL | 21.0766 mL | |
| 5 mM | 0.4215 mL | 2.1077 mL | 4.2153 mL | |
| 10 mM | 0.2108 mL | 1.0538 mL | 2.1077 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. |
Acute lung injury (ALI) in vivo model in mice. a) Schematic representation of the experimental rationale.ChemMedChem. 2015 Jul;10(7):1163-73. |
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