ensifentrine   Click here for help

GtoPdb Ligand ID: 11865

Synonyms: Ohtuvayre® | RPL554 | VMX 554 | VMX-554 | VMX554
Approved drug Immunopharmacology Ligand
ensifentrine is an approved drug (FDA (2024))
Compound class: Synthetic organic
Comment: Ensifentrine (RPL-554) is an inhibitor of phosphodiesterases 3 and 4 (PDE3 and PDE4) [3]. It has bronchodilatory action that is mediated by inhibition of PDE3 in airway smooth muscle [9,11] that is associated with short-term improvement in lung function [5]. Ensifentrine was developed for therapeutic potential in asthma and chronic obstructive pulmonary disease (COPD) [6-7]. It also also has anti-inflammatory effects in vitro (e.g. reducing TNFα release from human monocytes) and in vivo, likely through inhibtion of PDE4 expressed by inflammatory cells in the lungs [10]. Ensifentrine is active when delivered orally or by inhalation (nebulised) [2].

COVID-19: A pilot study of ensifentrine in hospitalised COVID-19 patients was initiated in mid-late 2020, but by 2024 no results had been published.

FDA approval of ensifentrine in 2024 made this the first COPD inhalation drug with a new mechanism of action to reach the clinic in more than 20 years.
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 4
Hydrogen bond donors 2
Rotatable bonds 7
Topological polar surface area 112.87
Molecular weight 477.24
XLogP 3.7
No. Lipinski's rules broken 0

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES COc1cc2c(cc1OC)CCn1c2cc(=Nc2c(C)cc(cc2C)C)n(c1=O)CCNC(=O)N
Isomeric SMILES Cc1cc(c(c(c1)C)N=c1cc2c3cc(c(cc3CCn2c(=O)n1CCNC(=O)N)OC)OC)C
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)
InChI Key CSOBIBXVIYAXFM-UHFFFAOYSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
No information available.
Summary of Clinical Use Click here for help
Ensifentrine (RPL-554) was progressed to clinical evaluation in patients with the airway diseases asthma and COPD. During the SARS-CoV-2 pandemic it was investigated for clinical efficacy in patients hospitalised with COVID-19. First FDA approval was granted in June 2024, as a nebuliser-delivered formulation to treat COPD [8].
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT04527471 Study of Ensifentrine or Placebo Delivered Via pMDI in Hospitalized Patients With COVID-19 Phase 2 Interventional Verona Pharma plc
NCT00001693 Phase I-II Multiple-Dose Safety and Efficacy Study of a Selective Inhibitor of Cyclooxygenase - 2 (SC-58635) in Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Patients and Carriers Phase 1 Interventional National Institutes of Health Clinical Center (CC) 12
NCT04542057 A Phase 3 Trial to Evaluate the Safety and Efficacy of Ensifentrine in Patients With COPD Phase 3 Interventional Verona Pharma plc 1
NCT04535986 A Phase 3 Clinical Trial to Evaluate the Safety and Efficacy of Ensifentrine in Patients With COPD Phase 3 Interventional Verona Pharma plc 1