| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| Other Sizes |
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 Vitro |
BAY 85-8501 is a potent and selective inhibitor of human neutrophil elastase (HNE). Its inhibitory constant (Ki) against HNE is 0.08 nM. [1]
It exhibits species selectivity, with Ki values of 8.0 nM against rodent neutrophil elastase (RNE) and 6.0 nM against murine neutrophil elastase (MNE). [1] In a biochemical inhibition assay conducted in the presence of 1 mM hydrogen peroxide (to mimic oxidative stress in an inflammatory environment), the IC50 of BAY 85-8501 shifted only 2-fold to 140 pM, indicating good oxidative stability. [1] BAY 85-8501 showed no inhibition (IC50 > 30,000 nM) against a panel of 21 related serine proteases, confirming high selectivity. [1] Binding kinetics analysis revealed an on-rate (k_on) of 12.6 x 10^6 M^{-1}s^{-1}, an off-rate (k_off) of 1.0 x 10^{-3} s^{-1}, and a residence time of approximately 0.3 hours (~17 minutes). [1] The compound showed no inhibitory potency (IC50 > 50 μM) against human cytochrome P450 isoforms CYP2C9 and CYP3A4. [1] |
|---|---|
| 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].
In a mouse acute lung injury (ALI) model induced by intratracheal instillation of HNE, oral administration of BAY 85-8501 (0.01, 0.03, 0.1 mg/kg) 1 hour prior to the challenge completely prevented lung injury and subsequent inflammation. A significant decrease in bronchoalveolar lavage fluid (BALF) hemoglobin concentration (indicative of lung hemorrhage) was observed at 0.01 mg/kg, and a significant reduction in BALF neutrophil count (indicative of inflammation) was observed at 0.1 mg/kg. [1] In a second ALI model induced by porcine pancreatic elastase (PPE, which BAY 85-8501 does not inhibit), the compound still showed efficacy against the secondary, MNE-driven inflammation and injury, but at approximately 30-fold higher doses (1 and 3 mg/kg p.o.), consistent with its lower potency against MNE (Ki = 6 nM). [1] |
| Enzyme Assay |
The inhibitory capacity of test compounds against HNE was assessed using functional biochemical assays with the isolated enzyme. IC50 values were derived from enzyme activity data (pH 7.4) in the presence or absence of various compound concentrations by applying a suitable fluorogenic peptide substrate, MeOSuc-AAPV-AMC. [1]
For Ki determination, enzyme reaction velocities were measured with different substrate concentrations at various inhibitor concentrations, and the inhibition constants (Ki) were extrapolated from Dixon plots, confirming competitive inhibition. [1] The on-rates (k_on) for elastase inhibitors binding to the target were determined using a functional biochemical assay with a substrate bearing a modified fluorescent label (MeOSuc-AAPV-umbelliferyl), allowing sensitive detection of substrate hydrolysis on a millisecond timescale. Nonlinear regression of reaction progress curves yielded the observed rate constant for the onset of inhibition. [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, midazolam for CYP3A4). IC50 values were derived from enzyme activity data in the presence/absence of various compound concentrations. [1] |
| Animal Protocol |
Acute Lung Injury (ALI) Model in Mice: Mice were administered BAY 85-8501 orally (p.o., gavage) at doses of 0.01, 0.03, 0.1, 1, or 3 mg/kg, formulated in a vehicle (specific vehicle not detailed for efficacy studies). One hour after compound administration, acute lung injury was induced by intratracheal instillation of either human neutrophil elastase (HNE) or porcine pancreatic elastase (PPE). One hour after the elastase challenge, animals were euthanized, and bronchoalveolar lavage fluid (BALF) was collected. Primary injury was quantified by measuring hemoglobin concentration in BALF, and inflammation was quantified by neutrophil count in BALF. [1]
Pharmacokinetic Studies in Rats: The pharmacokinetic profile was assessed following intravenous (0.25–2 hour infusion) and oral (gavage) administration of BAY 85-8501 at a dose of 0.3 mg/kg. For oral administration, the compound was formulated in vehicles including EtOH/PEG400/H2O or as a suspension in 0.5% Tylose. [1] |
| ADME/Pharmacokinetics |
In rats, after intravenous injection (0.3 mg/kg), the total plasma clearance (CL) of BAY 85-8501 was 0.5 L h⁻¹ kg⁻¹, the apparent steady-state volume of distribution (Vss) was 5.8 L kg⁻¹, and the terminal half-life (t⁻¹/²) was 8.5 h. [1]
The oral bioavailability (F) in rats was 63% at a dose of 0.3 mg/kg administered as a 0.5% Tyros suspension. [1] Assessment of the metabolic stability of the precursor compound in rat hepatocytes indicated that the introduction of an electron-withdrawing sulfone substituent at the C2' position of BAY 85-8501 contributes to metabolic stability. [1] |
| References | |
| Additional Infomation |
BAY 85-8501 ((4S)-4-(4-cyano-2-(methanesulfonyl)phenyl)-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-nitrile) is a small molecule inhibitor based on dihydropyrimidine ketones. [1] Its high efficiency and selectivity are achieved by strategically locking the bioactive conformation: introducing a methyl group at the N3 position of the north-phenyl ring and a methyl sulfone substituent at the C2' position, thereby pre-organizing the molecular structure to achieve optimal binding. [1] The compound binds to HNE via an induced-fit mechanism, in which the S2 subsite of the enzyme expands to accommodate the north-cyanophenyl moiety of the inhibitor. [1]
BAY 85-8501 is described as a clinical candidate drug that, at the time of publication, was undergoing clinical trials (a safety and efficacy trial, NCT01818544) for the treatment of lung diseases such as bronchiectasis. [1] |
| Molecular Formula |
C22H17F3N4O3S
|
|---|---|
| Molecular Weight |
474.455593824387
|
| Exact Mass |
474.097
|
| CAS # |
1161921-82-9
|
| Related CAS # |
(R)-BAY-85-8501;2446175-39-7
|
| PubChem CID |
66601502
|
| Appearance |
White to off-white solid powder
|
| Density |
1.5±0.1 g/cm3
|
| Boiling Point |
626.7±55.0 °C at 760 mmHg
|
| Flash Point |
332.8±31.5 °C
|
| Vapour Pressure |
0.0±1.8 mmHg at 25°C
|
| Index of Refraction |
1.622
|
| LogP |
1.99
|
| Hydrogen Bond Donor Count |
0
|
| Hydrogen Bond Acceptor Count |
8
|
| Rotatable Bond Count |
3
|
| Heavy Atom Count |
33
|
| Complexity |
1030
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
CC1=C([C@H](N(C(=O)N1C2=CC=CC(=C2)C(F)(F)F)C)C3=C(C=C(C=C3)C#N)S(=O)(=O)C)C#N
|
| InChi Key |
YAJWYFPMASPAMM-HXUWFJFHSA-N
|
| 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
|
| 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
|
| Synonyms |
BAY 858501; BAY858501; BAY-858501; BAY 85-8501; BAY85-8501; BAY-85-8501.
|
| 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)
|
| Solubility (In Vitro) |
DMSO : ~200 mg/mL (~421.53 mM)
|
|---|---|
| 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. |
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA
