Details
Stereochemistry | ACHIRAL |
Molecular Formula | C17H14Cl2F2N2O3 |
Molecular Weight | 403.208 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
C1CC1COc2cc(ccc2OC(F)F)C(=O)N=c3c(c[nH]cc3Cl)Cl
InChI
InChIKey=MNDBXUUTURYVHR-UHFFFAOYSA-N
InChI=1S/C17H14Cl2F2N2O3/c18-11-6-22-7-12(19)15(11)23-16(24)10-3-4-13(26-17(20)21)14(5-10)25-8-9-1-2-9/h3-7,9,17H,1-2,8H2,(H,22,23,24)
Molecular Formula | C17H14Cl2F2N2O3 |
Molecular Weight | 403.208 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
DescriptionCurator's Comment:: description was created based on several sources, including
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002398/WC500103075.pdf
Curator's Comment:: description was created based on several sources, including
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002398/WC500103075.pdf
Roflumilast is a specific phosphodiesterase type (4PDE4) inhibitor indicated for use as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL2093863 |
0.8 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Secondary | DALIRESP Approved UseIndicated as a treatment to reduce the risk of COPD exacerbations in patients with severe
COPD associated with chronic bronchitis and a history of exacerbations. Limitations of Use: DALIRESP is not a bronchodilator and is not indicated for the relief of acute bronchospasm. Launch Date1.29885117E12 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
12.5 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30538429 |
0.5 mg single, oral dose: 0.5 mg route of administration: Oral experiment type: SINGLE co-administered: |
ROFLUMILAST plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
65.1 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30538429 |
0.5 mg single, oral dose: 0.5 mg route of administration: Oral experiment type: SINGLE co-administered: |
ROFLUMILAST plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
19.9 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30538429 |
0.5 mg single, oral dose: 0.5 mg route of administration: Oral experiment type: SINGLE co-administered: |
ROFLUMILAST plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
17 h |
ROFLUMILAST plasma | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
Funbound
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
1% |
ROFLUMILAST plasma | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
450 ug 1 times / day steady, oral Recommended Dose: 450 ug, 1 times / day Route: oral Route: steady Dose: 450 ug, 1 times / day Sources: |
unhealthy, 64 years (range: 40-91 years) n = 4438 Health Status: unhealthy Condition: COPD Age Group: 64 years (range: 40-91 years) Sex: M+F Population Size: 4438 Sources: |
Disc. AE: Diarrhea, Nausea... AEs leading to discontinuation/dose reduction: Diarrhea (2.4%) Sources: Nausea (1.6%) |
5000 ug single, oral Highest studied dose Dose: 5000 ug Route: oral Route: single Dose: 5000 ug Sources: |
healthy, adult n = 1 Health Status: healthy Age Group: adult Population Size: 1 Sources: |
Other AEs: Headache, Gastrointestinal disorders... Other AEs: Headache (1 patient) Sources: Gastrointestinal disorders (1 patient) Dizziness (1 patient) Palpitations (1 patient) Lightheadedness (1 patient) Clamminess (1 patient) Arterial hypotension (1 patient) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Nausea | 1.6% Disc. AE |
450 ug 1 times / day steady, oral Recommended Dose: 450 ug, 1 times / day Route: oral Route: steady Dose: 450 ug, 1 times / day Sources: |
unhealthy, 64 years (range: 40-91 years) n = 4438 Health Status: unhealthy Condition: COPD Age Group: 64 years (range: 40-91 years) Sex: M+F Population Size: 4438 Sources: |
Diarrhea | 2.4% Disc. AE |
450 ug 1 times / day steady, oral Recommended Dose: 450 ug, 1 times / day Route: oral Route: steady Dose: 450 ug, 1 times / day Sources: |
unhealthy, 64 years (range: 40-91 years) n = 4438 Health Status: unhealthy Condition: COPD Age Group: 64 years (range: 40-91 years) Sex: M+F Population Size: 4438 Sources: |
Arterial hypotension | 1 patient | 5000 ug single, oral Highest studied dose Dose: 5000 ug Route: oral Route: single Dose: 5000 ug Sources: |
healthy, adult n = 1 Health Status: healthy Age Group: adult Population Size: 1 Sources: |
Clamminess | 1 patient | 5000 ug single, oral Highest studied dose Dose: 5000 ug Route: oral Route: single Dose: 5000 ug Sources: |
healthy, adult n = 1 Health Status: healthy Age Group: adult Population Size: 1 Sources: |
Dizziness | 1 patient | 5000 ug single, oral Highest studied dose Dose: 5000 ug Route: oral Route: single Dose: 5000 ug Sources: |
healthy, adult n = 1 Health Status: healthy Age Group: adult Population Size: 1 Sources: |
Gastrointestinal disorders | 1 patient | 5000 ug single, oral Highest studied dose Dose: 5000 ug Route: oral Route: single Dose: 5000 ug Sources: |
healthy, adult n = 1 Health Status: healthy Age Group: adult Population Size: 1 Sources: |
Headache | 1 patient | 5000 ug single, oral Highest studied dose Dose: 5000 ug Route: oral Route: single Dose: 5000 ug Sources: |
healthy, adult n = 1 Health Status: healthy Age Group: adult Population Size: 1 Sources: |
Lightheadedness | 1 patient | 5000 ug single, oral Highest studied dose Dose: 5000 ug Route: oral Route: single Dose: 5000 ug Sources: |
healthy, adult n = 1 Health Status: healthy Age Group: adult Population Size: 1 Sources: |
Palpitations | 1 patient | 5000 ug single, oral Highest studied dose Dose: 5000 ug Route: oral Route: single Dose: 5000 ug Sources: |
healthy, adult n = 1 Health Status: healthy Age Group: adult Population Size: 1 Sources: |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 6.0 |
no | |||
Page: 6.0 |
no | |||
Page: 6.0 |
no | |||
Page: 6.0 |
no | |||
Page: 54.0 |
no | |||
Page: 6.0 |
no | |||
Page: 6.0 |
no | |||
Page: 6.0 |
no | |||
Page: 6.0 |
no | |||
Page: 6.0 |
no | |||
Page: 6.0 |
no | |||
Page: 6.0 |
no | |||
Page: 6.0 |
no | |||
Page: 54.0 |
no | |||
Page: 6.0 |
no | |||
Page: 6.0 |
no | |||
Page: 54.0 |
no | |||
Page: 54.0 |
no | |||
Page: 6.0 |
no | |||
Page: 4.0 |
no | |||
Page: 6.0 |
weak |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 3.0 |
major | yes (co-administration study) Comment: fluvoxamine increased roflumilast cmax 12%, auc 156%; enoxacin increased roflumilast cmax 20%, auc 56%; cimetadine increased roflumilast cmax 46%, auc 85% Page: 3.0 |
||
Page: 3.0 |
major | yes (co-administration study) Comment: erythromycin increased roflumilast cmax 40% and auc 70%; ketoconazole increased roflumilast cmax 23%, auc 99%; rifampicin decreased roflumilast cmax 68%, auc 80% Page: 3.0 |
||
Page: 52.0 |
no | |||
Page: 52.0 |
no | |||
Page: 52.0 |
no | |||
Page: 52.0 |
no | |||
Page: 52.0 |
no | |||
Page: 52.0 |
no | |||
Page: 52.0 |
no | |||
Page: 52.0 |
no | |||
Page: 52.0 |
no | |||
Page: 5.0 |
no |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 81.0 |
PubMed
Title | Date | PubMed |
---|---|---|
Roflumilast for asthma and chronic obstructive pulmonary disease. | 2005 Oct |
|
Phosphodiesterase 4 inhibitors for the treatment of asthma and COPD. | 2006 |
|
Phosphodiesterase type 4 inhibitors cause proinflammatory effects in vivo. | 2006 Oct |
|
Treating COPD with PDE 4 inhibitors. | 2007 |
|
Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. | 2007 Dec |
|
Effects of roflumilast, a phosphodiesterase-4 inhibitor, on hypoxia- and monocrotaline-induced pulmonary hypertension in rats. | 2009 Jul |
|
Quinolines as a novel structural class of potent and selective PDE4 inhibitors: optimisation for oral administration. | 2009 Mar 1 |
|
[Pharmacological profile of roflumilast]. | 2010 Dec |
|
Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. | 2011 May 11 |
|
Simultaneous quantitation of IC87114, roflumilast and its active metabolite roflumilast N-oxide in plasma by LC-MS/MS: application for a pharmacokinetic study. | 2012 Dec |
|
Roflumilast inhibits the release of chemokines and TNF-α from human lung macrophages stimulated with lipopolysaccharide. | 2012 Mar |
|
The molecular basis for the inhibition of phosphodiesterase-4D by three natural resveratrol analogs. Isolation, molecular docking, molecular dynamics simulations, binding free energy, and bioassay. | 2013 Oct |
Patents
Sample Use Guides
The recommended dosage for patients with COPD is one 500 ug tablet per day, with or without food.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=17704822
To study the potency of roflumilast to inhibit adhesion of PMNL (polymorphonuclear leukocytes isolated from human peripheral venous blood) to TNFa-prestimulated HUVEC (human umbilical vein endothelial cells isolated from human umbilical cords) endothelial cell monolayers were stimulated with 0.3 ng/ml1 TNFa for 3 h. Medium was removed and roflumilast (10 pM–1 mM) was added followed by PMNL (50 000 cells per well) addition for 30 min. Roflumilast reduced adherence of PMNL to HUVEC with IC50 of 3.2 nM.
Substance Class |
Chemical
Created
by
admin
on
Edited
Sat Jun 26 08:02:59 UTC 2021
by
admin
on
Sat Jun 26 08:02:59 UTC 2021
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Record UNII |
0P6C6ZOP5U
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Record Status |
Validated (UNII)
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Record Version |
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WHO-ATC |
R03DX07
Created by
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LIVERTOX |
859
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EMA ASSESSMENT REPORTS |
DAXAS (AUTHORIZED: PULMONARY DISEASE, CHRONIC OBSTRUCTIVE )
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WHO-VATC |
QR03DX07
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NDF-RT |
N0000182961
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NCI_THESAURUS |
C744
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EMA ASSESSMENT REPORTS |
DALIRESP (AUTHORIZED: PULMONARY DISEASE, CHRONIC OBSTRUCTIVE )
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EMA ASSESSMENT REPORTS |
LIBERTEK (AUTHORIZED: PULMONARY DISEASE, CHRONIC OBSTRUCTIVE)
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C76890
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7598
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6962
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162401-32-3
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0P6C6ZOP5U
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162401-32-3
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C424423
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ROFLUMILAST
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M9648
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PRIMARY | Merck Index | ||
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N0000182960
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PRIMARY | Phosphodiesterase 4 Inhibitors [MoA] | ||
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3531
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DB01656
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1091836
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CHEMBL193240
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Roflumilast
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SUB10358MIG
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449193
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METABOLIC ENZYME -> SUBSTRATE | |||
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BINDER->LIGAND |
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EXCRETED UNCHANGED |
The major route of elimination for roflumilast is through hepatic metabolism. Roflumilast was not detectable in urine. Roflumilast N-oxide was only a trace metabolite in urine (less than 1%).
URINE
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METABOLIC ENZYME -> SUBSTRATE | |||
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METABOLIC ENZYME -> SUBSTRATE | |||
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TARGET -> INHIBITOR |
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METABOLITE -> PARENT | |||
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METABOLITE ACTIVE -> PARENT |
MAJOR
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METABOLITE INACTIVE -> PARENT |
conjugated metabolite
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ACTIVE MOIETY |
Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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Tmax | PHARMACOKINETIC |
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Volume of Distribution | PHARMACOKINETIC |
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Biological Half-life | PHARMACOKINETIC |
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