Ensifentrine

Identification

Summary

Ensifentrine is a phosphodiesterase inhibitor used for the maintenance treatment of chronic obstructive pulmonary disease (COPD) in adults.

Brand Names
Ohtuvayre
Generic Name
Ensifentrine
DrugBank Accession Number
DB16157
Background

Ensifentrine is a first-in-class, selective dual inhibitor of the phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) enzymes.6 On June 26, 2024, the FDA announced the approval of an inhaled product of ensifentrine for the treatment of chronic obstructive pulmonary disease (COPD) in adults, which allows the drug to be directly delivered to the lungs.6 It works to induce bronchodilator and reduce inflammation in COPD.3

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 477.565
Monoisotopic: 477.237604498
Chemical Formula
C26H31N5O4
Synonyms
  • 2-(9,10-DIMETHOXY-4-OXO-2-(2,4,6-TRIMETHYLPHENYL)IMINO-6,7-DIHYDROPYRIMIDO(6,1-A)ISOQUINOLIN-3-YL)ETHYLUREA
  • Ensifentrine
  • N-(2-((2E)-9,10-DIMETOXI-4-OXO-2-((2,4,6-TRIMETILFENIL)IMINO)-6,7-DIHIDRO-2H-PIRIMIDO(6,1-A)ISOQUINOLEIN-3(4H)-IL)ETIL)UREA
  • UREA, N-(2-(6,7-DIHYDRO-9,10-DIMETHOXY-4-OXO-2-((2,4,6-TRIMETHYLPHENYL)IMINO)-2H-PYRIMIDO(6,1-A)ISOQUINOLIN-3(4H)-YL)ETHYL)-
External IDs
  • LS-193,855
  • LS-193855
  • RPL 554
  • RPL-554
  • RPL554

Pharmacology

Indication

Ensifentrine is indicated for the maintenance treatment of chronic obstructive pulmonary disease (COPD) in adult patients.5

Reduce drug development failure rates
Build, train, & validate machine-learning models
with evidence-based and structured datasets.
See how
Build, train, & validate predictive machine-learning models with structured datasets.
See how
Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Management ofChronic obstructive pulmonary disease (copd)•••••••••••••••••
Associated Therapies
Contraindications & Blackbox Warnings
Prevent Adverse Drug Events Today
Tap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.
Learn more
Avoid life-threatening adverse drug events with our Clinical API
Learn more
Pharmacodynamics

Ensifentrine causes bronchodilation in chronic obstructive pulmonary disease (COPD) and asthma.1 Ensifentrine was shown to mediate anti-inflammatory effects by reducing the levels of proinflammatory cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) in cystic fibrosis bronchial epithelial cells.1

In vitro, ensifentrine activates the CFTR-mediated chloride ion secretion in bronchial epithelial cells, increasing ciliary beat frequency and potentially enhancing mucociliary clearance.3 In guinea pig models, ensifentrine demonstrated bronchoprotective properties against airway constriction caused by spasmogens and antigens: It caused dose-dependent relaxation of the airways.3,4

Mechanism of action

COPD is characterized by progressive airflow obstruction and chronic inflammation of the respiratory tract. Because PDE3 and PDE4 are expressed in airway smooth muscle, inflammatory cells, and bronchial epithelial cells to drive inflammation and bronchial muscle tone, these two PDE isoforms have been identified as therapeutic targets in the treatment of COPD.3 PDE3 primarily hydrolyzes the second-messenger molecule cyclic adenosine monophosphate (cAMP) in airway smooth muscle, mediating muscle tone.2,3 PDE3 can also hydrolyze cyclic guanosine monophosphate (cGMP).2 PDE4 regulates cAMP only and is involved in inflammatory cell activation and migration, as well as Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) stimulation in bronchial epithelial cells.2,3,4

Ensifentrine is a drug that selectively inhibits the PDE3 and PDE4 enzymes.5 Dual inhibition of PDE3 and PDE4 results in the accumulation of intracellular levels of cAMP and/or cGMP, causing a synergistic effect in contracting airway smooth muscle and suppressing inflammatory response.2,5

TargetActionsOrganism
APhosphodiesterase 3
inhibitor
Humans
APhosphodiesterase 4
inhibitor
Humans
Absorption

Following inhaled administration of ensifentrine in healthy subjects and subjects with COPD, ensifentrine Cmax was attained around 0.6 to 1.5 hours after dosing. A randomized, two-period, cross-over study assessing systemic exposure following inhalation of two times the recommended dose of ensifentrine with and without charcoal block demonstrated that the majority of an inhaled dose (approximately 90%) is delivered to the lung from which it is absorbed.5

Population pharmacokinetic analysis indicates that relative bioavailability in subjects with COPD is approximately 35% lower when compared to healthy subjects. Exposure to ensifentrine was associated with high inter-subject variability.5

Volume of distribution

Apparent central and peripheral volume of distribution for ensifentrine in healthy subjects were 2700 L and 1820 L, respectively, as estimated in population PK analysis. In patients with COPD, apparent central and peripheral volumes were estimated as 8150 L and 5490 L, respectively.5

Protein binding

In vitro plasma protein binding of ensifentrine is approximately 90%.5

Metabolism

Following administration of a single nebulized dose, 8 times the recommended dose of ensifentrine, unchanged ensifentrine was identified as the major drug-related component in human plasma, accounting for 96 and 99% of the drug-related material identified in Tmax and time normalized (0-24 h) plasma samples, respectively. The primary metabolic routes for ensifentrine are oxidative (hydroxylation, O-demethylation) followed by conjugation (e.g., glucuronidation). In vitro results indicate that, at physiologically relevant concentrations, ensifentrine was predominantly metabolized by CYP2C9 and to a lesser extent by CYP2D6.5

Route of elimination

The majority of ensifentrine is excreted in feces. After a 3 mg nebulized dose, urinary elimination of unchanged ensifentrine was negligible (<0.3% of the dose).5

Half-life

Following twice-daily administration for 6 days, terminal elimination half-life ranged from 10.6 to 12.6 hours in healthy subjects and subjects with COPD (1.5 mg to 12 mg twice daily).5

Clearance

Not Available

Adverse Effects
Improve decision support & research outcomes
With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!
See the data
Improve decision support & research outcomes with our structured adverse effects data.
See a data sample
Toxicity

There is no information regarding the lethal dose 50 of ensifentrine. An overdosage of ensifentrine may lead to signs and symptoms such as headache, tachycardia, and palpitations. Treatment of overdosage consists of temporary interruption of ensifentrine along with appropriate symptomatic and/or supportive therapy.5

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
Isosorbide mononitrateEnsifentrine may increase the hypotensive activities of Isosorbide mononitrate.
Food Interactions
No interactions found.

Products

Drug product information from 10+ global regions
Our datasets provide approved product information including:
dosage, form, labeller, route of administration, and marketing period.
Access now
Access drug product information from over 10 global regions.
Access now
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
OhtuvayreSuspension3 mg/2.5mLRespiratory (inhalation)Verona Pharma, Inc.2024-06-26Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
3E3D8T1GIX
CAS number
1884461-72-6
InChI Key
CSOBIBXVIYAXFM-BYNJWEBRSA-N
InChI
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+
IUPAC Name
{2-[(2E)-9,10-dimethoxy-4-oxo-2-[(2,4,6-trimethylphenyl)imino]-2H,3H,4H,6H,7H-pyrimido[4,3-a]isoquinolin-3-yl]ethyl}urea
SMILES
COC1=C(OC)C=C2C(CCN3C(=O)N(CCNC(N)=O)\C(C=C23)=N\C2=C(C)C=C(C)C=C2C)=C1

References

General References
  1. Turner MJ, Dauletbaev N, Lands LC, Hanrahan JW: The Phosphodiesterase Inhibitor Ensifentrine Reduces Production of Proinflammatory Mediators in Well Differentiated Bronchial Epithelial Cells by Inhibiting PDE4. J Pharmacol Exp Ther. 2020 Dec;375(3):414-429. doi: 10.1124/jpet.120.000080. Epub 2020 Oct 4. [Article]
  2. Anzueto A, Barjaktarevic IZ, Siler TM, Rheault T, Bengtsson T, Rickard K, Sciurba F: Ensifentrine, a Novel Phosphodiesterase 3 and 4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease: Randomized, Double-Blind, Placebo-controlled, Multicenter Phase III Trials (the ENHANCE Trials). Am J Respir Crit Care Med. 2023 Aug 15;208(4):406-416. doi: 10.1164/rccm.202306-0944OC. [Article]
  3. Donohue JF, Rheault T, MacDonald-Berko M, Bengtsson T, Rickard K: Ensifentrine as a Novel, Inhaled Treatment for Patients with COPD. Int J Chron Obstruct Pulmon Dis. 2023 Jul 28;18:1611-1622. doi: 10.2147/COPD.S413436. eCollection 2023. [Article]
  4. Faruqi MA, Khan MMKS, Mannino DM: Perspectives on Ensifentrine and Its Therapeutic Potential in the Treatment of COPD: Evidence to Date. Int J Chron Obstruct Pulmon Dis. 2024 Jan 3;19:11-16. doi: 10.2147/COPD.S385811. eCollection 2024. [Article]
  5. FDA Approved Drug Products: OHTUVAYRE (ensifentrine) inhalation suspension, for oral inhalation use [Link]
  6. Verona Pharma: Verona Pharma Announces US FDA Approval of Ohtuvayre™ (ensifentrine) [Link]
ChemSpider
8110374
RxNav
2687215
ChEMBL
CHEMBL4594287
ZINC
ZINC000000602859
Wikipedia
Ensifentrine

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
3CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)2somestatusstop reasonjust information to hide
3RecruitingTreatmentChronic Obstructive Pulmonary Disease (COPD)2somestatusstop reasonjust information to hide
2CompletedTreatmentAsthma1somestatusstop reasonjust information to hide
2CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)6somestatusstop reasonjust information to hide
2CompletedTreatmentCoronavirus Disease 2019 (COVID‑19) / Infections, Coronavirus1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
SuspensionRespiratory (inhalation)3 mg/2.5mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9956171No2015-09-152035-09-15US flag
US9062047No2011-08-212031-08-21US flag
US10945950No2015-09-152035-09-15US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0218 mg/mLALOGPS
logP3.12ALOGPS
logP3.27Chemaxon
logS-4.3ALOGPS
pKa (Strongest Acidic)14.74Chemaxon
pKa (Strongest Basic)5.23Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area109.49 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity137.62 m3·mol-1Chemaxon
Polarizability52.81 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-004i-0000900000-99596635c6ac65c94072
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-056r-0000900000-130cc4dc89e8cd6cd45c
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-02br-0000900000-603aa7243cdf4d761bb8
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0006-4002900000-02b21be3458d5852eda3
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0gb9-0115900000-18e78d6f1953405ac22c
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-000x-4003900000-d00ef3296d039c495f12
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-233.8289078
predicted
DarkChem Lite v0.1.0
[M+H]+232.9659078
predicted
DarkChem Lite v0.1.0
[M+Na]+234.4190078
predicted
DarkChem Lite v0.1.0

Targets

Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
Learn more
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
Learn more
Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Cyclic nucleotide phosphodiesterase with specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes (PubMed:1315035, PubMed:25961942, PubMed:8155697, PubMed:8695850). Has also activity toward cUMP (PubMed:27975297). Independently of its catalytic activity it is part of an E2/17beta-estradiol-induced pro-apoptotic signaling pathway. E2 stabilizes the PDE3A/SLFN12 complex in the cytosol, promoting the dephosphorylation of SLFN12 and activating its pro-apoptotic ribosomal RNA/rRNA ribonuclease activity. This apoptotic pathway might be relevant in tissues with high concentration of E2 and be for instance involved in placenta remodeling (PubMed:31420216, PubMed:34707099)
Specific Function
3',5'-cyclic-AMP phosphodiesterase activity

Components:
References
  1. Donohue JF, Rheault T, MacDonald-Berko M, Bengtsson T, Rickard K: Ensifentrine as a Novel, Inhaled Treatment for Patients with COPD. Int J Chron Obstruct Pulmon Dis. 2023 Jul 28;18:1611-1622. doi: 10.2147/COPD.S413436. eCollection 2023. [Article]
  2. Faruqi MA, Khan MMKS, Mannino DM: Perspectives on Ensifentrine and Its Therapeutic Potential in the Treatment of COPD: Evidence to Date. Int J Chron Obstruct Pulmon Dis. 2024 Jan 3;19:11-16. doi: 10.2147/COPD.S385811. eCollection 2024. [Article]
  3. FDA Approved Drug Products: OHTUVAYRE (ensifentrine) inhalation suspension, for oral inhalation use [Link]
Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Hydrolyzes the second messenger 3',5'-cyclic AMP (cAMP), which is a key regulator of many important physiological processes
Specific Function
3',5'-cyclic-AMP phosphodiesterase activity

Components:
References
  1. Donohue JF, Rheault T, MacDonald-Berko M, Bengtsson T, Rickard K: Ensifentrine as a Novel, Inhaled Treatment for Patients with COPD. Int J Chron Obstruct Pulmon Dis. 2023 Jul 28;18:1611-1622. doi: 10.2147/COPD.S413436. eCollection 2023. [Article]
  2. Faruqi MA, Khan MMKS, Mannino DM: Perspectives on Ensifentrine and Its Therapeutic Potential in the Treatment of COPD: Evidence to Date. Int J Chron Obstruct Pulmon Dis. 2024 Jan 3;19:11-16. doi: 10.2147/COPD.S385811. eCollection 2024. [Article]
  3. FDA Approved Drug Products: OHTUVAYRE (ensifentrine) inhalation suspension, for oral inhalation use [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:15766564, PubMed:19965576, PubMed:7574697, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9435160, PubMed:9866708). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031)
Specific Function
(R)-limonene 6-monooxygenase activity
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. FDA Approved Drug Products: OHTUVAYRE (ensifentrine) inhalation suspension, for oral inhalation use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants
Specific Function
anandamide 11,12 epoxidase activity
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. FDA Approved Drug Products: OHTUVAYRE (ensifentrine) inhalation suspension, for oral inhalation use [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
Specific Function
ABC-type xenobiotic transporter activity
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
Broad substrate specificity ATP-binding cassette transporter ABCG2
Molecular Weight
72313.47 Da
References
  1. FDA Approved Drug Products: OHTUVAYRE (ensifentrine) inhalation suspension, for oral inhalation use [Link]

Drug created at December 15, 2020 18:14 / Updated at August 08, 2024 23:11