PDE

Important Safety Information
Indications
Ohtuvayre is a prescription medicine used to treat chronic obstructive pulmonary disease (COPD) in adults. COPD is a chronic (long-term) lung disease that includes chronic bronchitis, emphysema, or both.
What is the most important information I should know about Ohtuvayre?
Ohtuvayre may cause serious side effects, including:
Shortness of breath immediately after inhaling the medication. If you experience shortness of breath immediately after inhaling the medication, stop using Ohtuvayre right away and call your healthcare provider or go to the nearest hospital emergency room immediately. Mental health problems, including suicidal thoughts and behaviors. You may experience mood or behavioral changes while taking Ohtuvayre. If you experience any of the following symptoms, contact your healthcare provider right away, especially if these symptoms are new, worsening, or worrying: thoughts of suicide or death, suicide attempts, difficulty sleeping (insomnia), new or worsening anxiety, new or worsening depression, dangerous impulsive behavior, and/or other unusual changes in behavior or mood. Do not use Ohtuvayre to treat sudden difficulty breathing. Always carry an emergency inhaler with you.
Who should not use Ohtuvayre?
Do not use Ohtuvayre if you have an allergic reaction to entifentlin or any of the ingredients in Ohtuvayre.
What should I tell my healthcare provider before using Ohtuvayre?
Before using Ohtuvayre, tell your healthcare professional if you have or have had a history of mental health problems, including depression and suicidal behavior; if you have liver problems; if you are pregnant or planning to become pregnant; or if you are breastfeeding. It is currently unknown whether Ohtuvayre can harm an unborn baby. It is currently unknown whether any of the drug ingredients in Ohtuvayre pass into breast milk and whether this can harm the baby.
Inform your healthcare provider about any medications you are taking, including prescription drugs, over-the-counter drugs, vitamins, and herbal supplements.
What are the most common side effects of Ohtuvayre?
The most common side effects of Ohtuvayre include back pain, high blood pressure, bladder infection, and diarrhea.
https://www.veronapharma.com/news/verona-pharma-announces-us-fda-approval-of-ohtuvayre-ensifentrine/

Ensifentrine is currently undergoing clinical trial NCT04535986 (a Phase III clinical trial evaluating the safety and efficacy of ensifentrine in COPD patients). Ensifentrine is an inhaled phosphodiesterase (PDE) inhibitor that inhibits type 3 (PDE3) and type 4 (PDE4) phosphodiesterases, possessing potential anti-inflammatory and bronchodilatory effects. After administration, ensifentrine targets, binds to, and inhibits PDE3 and PDE4, thereby increasing intracellular cyclic adenosine monophosphate (cAMP) levels and cAMP-mediated signaling. This may lead to bronchial smooth muscle relaxation and modulate the inflammatory response. PDE3 and PDE4 are members of the PDE superfamily that hydrolyze cAMP and 3',5'-cyclic guanosine monophosphate (cGMP) to inactive 5' monophosphate. PDE3 is the most widely 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.

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Mechanism of Action
Ensifentelin is a dual inhibitor of phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4); it is also an activator of cystic fibrosis transmembrane conduction regulator (CFTR). Due to its dual inhibitory effect, the drug has bronchodilatory and anti-inflammatory properties; due to CFTR activation, it also reduces mucus viscosity and improves mucociliary clearance. Ensifentelin is currently being investigated for chronic obstructive pulmonary disease (COPD), cystic fibrosis, asthma, other respiratory diseases, and COVID-19.

C26H31N5O4

477.238

C, 65.39; H, 6.54; N, 14.67; O, 13.40

298680-25-8

Ensifentrine;1884461-72-6; 3098314-20-3

9934746

Typically exists as solid at room temperature

3.62

2

5

6

35

849

0

O=C1N(CCNC(N)=O)/C(/C=C2C3C=C(C(=CC=3CCN21)OC)OC)=N/C1C(C)=CC(C)=CC=1C

CSOBIBXVIYAXFM-UHFFFAOYSA-N

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)

2-[9,10-dimethoxy-4-oxo-2-(2,4,6-trimethylphenyl)imino-6,7-dihydropyrimido[6,1-a]isoquinolin-3-yl]ethylurea

RPL-554; RPL-554; RPL-554

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)