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Purity: ≥98%
Ensifentrine (RPL-554) is a novel and potent PDE-phosphodiesterase inhibitor with bronchoprotective and anti-inflammatory activities. Specifically, it is an inhaled first-in-class dual inhibitor of PDE3/4 with IC50s of 0.4 nM and 1479 nM, respectively. Ensifentrine has the potential to be used for treating chronic obstructive pulmonary disease (COPD).
| ln Vitro |
Ensifentrine (RPL-554) suppresses human monocytes' TNF-α release produced by lipopolysaccharide (IC50 of 0.52 μM) and their proliferation in response to phytohemagglutinin (IC50 of 0.46 μM) in a concentration-dependent manner[1]. Ensifentrine (10 μM) effectively inhibits the contraction of isolated tracheal preparations from superfused guinea pigs that is caused by electrical field stimulation. After superfusion ends, contractile responses are inhibited for up to 12 hours, with RPL-554 exhibiting a prolonged duration of action[1].
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| ln Vivo |
Ensifentrine (RPL-554; 10 mg/kg; oral dose; once) in ovalbumin-sensitized guinea pigs dramatically reduces eosinophil recruitment after antigen challenge[1]. The recruitment of eosinophils to the airways is dramatically inhibited when conscious guinea pigs inhale a dry powder containing ensefentrine (25% in micronized lactose) 1.5 hours prior to antigen exposure[1]. Over the course of 5.5 hours, conscious guinea pigs exposed to dry powder containing 2.5% ensefentrine in micronized lactose are shown to exhibit a considerable inhibition of histamine-induced bronchoconstriction and plasma protein extravasation in the trachea[1].
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| Animal Protocol |
Animal/Disease Models: Male Dunkin Hartley guinea pigs (200-300 g) injected with ovalbumin[1].
Doses: 10 mg/kg Route of Administration: Oral administration; once Experimental Results: Dramatically inhibits eosinophil recruitment following antigen challenge in ovalbumin-sensitized guinea pigs. |
| References |
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| Additional Infomation |
Ensifentrine is under investigation in clinical trial NCT04535986 (A Phase 3 Clinical Trial to Evaluate the Safety and Efficacy of Ensifentrine in Patients With COPD).
Ensifentrine is an inhaled inhibitor of the phosphodiesterase (PDE) types 3 (PDE3) and 4 (PDE4), with potential anti-inflammatory and bronchodilator activities. Upon administration, ensifentrine targets, binds to and inhibits PDE3 and PDE4, which leads to an increase of both intracellular levels of cyclic-3',5'-adenosine monophosphate (cAMP) and cAMP-mediated signaling. This may lead to bronchial smooth muscle relaxation and modulate inflammatory responses. PDE3 and PDE4, members of the PDE superfamily, hydrolyze cAMP and 3',5'-cyclic guanosine monophosphate (cGMP) to their inactive 5' monophosphates. PDE3 is the most expressed PDE isoenzyme in bronchial smooth muscle. PDE4 is expressed in immune cells including T-cells, monocytes, macrophages, neutrophils, dendritic cells and eosinophils. It plays an important role in inflammation, especially in inflammatory airway diseases. Mechanism of Action Ensifentrine is a dual inhibitor of phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4); it is also an activator of the cystic fibrosis transmembrane conductance regulator (CFTR). This drug has bronchodilatory and anti-inflammatory properties due to the dual inhibition; it also has mucous viscosity reduction and improved mucociliary clearance effects due to the CFTR activation. Ensifentrine is currently being investigated against COPD, cystic fibrosis, asthma, other respiratory diseases, and COVID-19. |
| Molecular Formula |
C26H31N5O4
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|---|---|
| Molecular Weight |
477.5554
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| Exact Mass |
477.237
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| CAS # |
1884461-72-6
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| Related CAS # |
(E/Z)-Ensifentrine;298680-25-8
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| PubChem CID |
9934746
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| Appearance |
Light yellow to green yellow solid powder
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| LogP |
2.7
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
35
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| Complexity |
849
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1N(C([H])([H])C([H])([H])N([H])C(N([H])[H])=O)/C(/C([H])=C2C3=C([H])C(=C(C([H])=C3C([H])([H])C([H])([H])N21)OC([H])([H])[H])OC([H])([H])[H])=N/C1C(C([H])([H])[H])=C([H])C(C([H])([H])[H])=C([H])C=1C([H])([H])[H]
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| InChi Key |
CSOBIBXVIYAXFM-BYNJWEBRSA-N
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| InChi Code |
InChI=1S/C26H31N5O4/c1-15-10-16(2)24(17(3)11-15)29-23-14-20-19-13-22(35-5)21(34-4)12-18(19)6-8-30(20)26(33)31(23)9-7-28-25(27)32/h10-14H,6-9H2,1-5H3,(H3,27,28,32)/b29-23+
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| Chemical Name |
N-(2-{(2E)-9,10-dimethoxy-4-oxo-2-[(2,4,6-
trimethylphenyl)imino]-6,7-dihydro-2H-pyrimido[6,1-
a]isoquinolin-3(4H)-yl}ethyl)urea
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| Synonyms |
Ensifentrine RPL-554 Ensifentrina RPL554 Ensifentrinum
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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 : ~25 mg/mL (~52.35 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.25 mg/mL (2.62 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 12.5 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: 1.25 mg/mL (2.62 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 12.5 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0940 mL | 10.4699 mL | 20.9398 mL | |
| 5 mM | 0.4188 mL | 2.0940 mL | 4.1880 mL | |
| 10 mM | 0.2094 mL | 1.0470 mL | 2.0940 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.
A Study to Evaluate the Pharmacokinetics, Safety and Tolerability of Nebulized Ensifentrine in Healthy Chinese Subjects
CTID: NCT05758428
Phase: Phase 1 Status: Completed
Date: 2023-04-24
Products are for research use only; We do not sell to patients
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