U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ACHIRAL
Molecular Formula C17H14Cl2F2N2O3
Molecular Weight 403.207
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of Roflumilast

SMILES

FC(F)OC1=C(OCC2CC2)C=C(C=C1)C(=O)NC3=C(Cl)C=NC=C3Cl

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)

HIDE SMILES / InChI

Description
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.

CNS Activity

Curator's Comment: Studies in rats with radiolabeled roflumilast indicate low penetration across the blood-brain barrier.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
0.8 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Secondary
DALIRESP

Approved Use

Indicated 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 Date

2011
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
12.5 ng/mL
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

AUC

ValueDoseCo-administeredAnalytePopulation
65.1 ng × h/mL
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

T1/2

ValueDoseCo-administeredAnalytePopulation
19.9 h
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

Funbound

ValueDoseCo-administeredAnalytePopulation
1%
ROFLUMILAST plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse 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%)
Nausea (1.6%)
Sources:
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)
Gastrointestinal disorders (1 patient)
Dizziness (1 patient)
Palpitations (1 patient)
Lightheadedness (1 patient)
Clamminess (1 patient)
Arterial hypotension (1 patient)
Sources:
AEs

AEs

AESignificanceDosePopulation
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:
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
weak
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
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
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
no
no
no
no
no
no
no
no
no
no
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Dynamic activation of cystic fibrosis transmembrane conductance regulator by type 3 and type 4D phosphodiesterase inhibitors.
2005 Aug
Roflumilast for asthma and chronic obstructive pulmonary disease.
2005 Oct
Phosphodiesterase 4 inhibitors for the treatment of asthma and COPD.
2006
Treating COPD with PDE 4 inhibitors.
2007
Phosphodiesterase 4 inhibitors augment levels of glucocorticoid receptor in B cell chronic lymphocytic leukemia but not in normal circulating hematopoietic cells.
2007 Aug 15
Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD.
2007 Dec
Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability.
2007 Oct
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
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.
Name Type Language
Roflumilast
DASH   EMA EPAR   INN   JAN   MART.   MI   ORANGE BOOK   USAN   VANDF   WHO-DD  
USAN   INN  
Official Name English
DAXAS
Brand Name English
3-(Cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)benzamide
Systematic Name English
ROFLUMILAST [MART.]
Common Name English
ROFLUMILAST [ORANGE BOOK]
Common Name English
ROFLUMILAST [JAN]
Common Name English
ROFLUMILAST [MI]
Common Name English
ROFLUMILAST [USAN]
Common Name English
Roflumilast [WHO-DD]
Common Name English
B9302-107
Code English
DALIRESP
Brand Name English
ROFLUMILAST [VANDF]
Common Name English
BY-217
Code English
BYK20869
Code English
ROFLUMILAST [EMA EPAR]
Common Name English
roflumilast [INN]
Common Name English
B-9302-107
Code English
ARQ-151
Code English
ARQ-154 (Roflumilast foam)
Code English
BY217
Code English
BYK-20869
Code English
Benzamide, 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-
Systematic Name English
ZORYVE
Brand Name English
Classification Tree Code System Code
WHO-ATC R03DX07
Created by admin on Fri Dec 15 16:35:09 GMT 2023 , Edited by admin on Fri Dec 15 16:35:09 GMT 2023
LIVERTOX NBK548195
Created by admin on Fri Dec 15 16:35:09 GMT 2023 , Edited by admin on Fri Dec 15 16:35:09 GMT 2023
EMA ASSESSMENT REPORTS DAXAS (AUTHORIZED: PULMONARY DISEASE, CHRONIC OBSTRUCTIVE )
Created by admin on Fri Dec 15 16:35:09 GMT 2023 , Edited by admin on Fri Dec 15 16:35:09 GMT 2023
WHO-VATC QR03DX07
Created by admin on Fri Dec 15 16:35:09 GMT 2023 , Edited by admin on Fri Dec 15 16:35:09 GMT 2023
NDF-RT N0000182961
Created by admin on Fri Dec 15 16:35:09 GMT 2023 , Edited by admin on Fri Dec 15 16:35:09 GMT 2023
NCI_THESAURUS C744
Created by admin on Fri Dec 15 16:35:09 GMT 2023 , Edited by admin on Fri Dec 15 16:35:09 GMT 2023
EMA ASSESSMENT REPORTS DALIRESP (AUTHORIZED: PULMONARY DISEASE, CHRONIC OBSTRUCTIVE )
Created by admin on Fri Dec 15 16:35:09 GMT 2023 , Edited by admin on Fri Dec 15 16:35:09 GMT 2023
EMA ASSESSMENT REPORTS LIBERTEK (AUTHORIZED: PULMONARY DISEASE, CHRONIC OBSTRUCTIVE)
Created by admin on Fri Dec 15 16:35:09 GMT 2023 , Edited by admin on Fri Dec 15 16:35:09 GMT 2023
Code System Code Type Description
NCI_THESAURUS
C76890
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PRIMARY
INN
7598
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PRIMARY
IUPHAR
6962
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PRIMARY
CAS
162401-32-3
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PRIMARY
FDA UNII
0P6C6ZOP5U
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PRIMARY
EPA CompTox
DTXSID8044123
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PRIMARY
MESH
C424423
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PRIMARY
USAN
OO-57
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PRIMARY
WIKIPEDIA
ROFLUMILAST
Created by admin on Fri Dec 15 16:35:09 GMT 2023 , Edited by admin on Fri Dec 15 16:35:09 GMT 2023
PRIMARY
MERCK INDEX
m9648
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PRIMARY Merck Index
NDF-RT
N0000182960
Created by admin on Fri Dec 15 16:35:09 GMT 2023 , Edited by admin on Fri Dec 15 16:35:09 GMT 2023
PRIMARY Phosphodiesterase 4 Inhibitors [MoA]
DRUG CENTRAL
3531
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PRIMARY
DRUG BANK
DB01656
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PRIMARY
SMS_ID
100000080252
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PRIMARY
RS_ITEM_NUM
1605012
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PRIMARY
RXCUI
1091836
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PRIMARY RxNorm
ChEMBL
CHEMBL193240
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PRIMARY
LACTMED
Roflumilast
Created by admin on Fri Dec 15 16:35:09 GMT 2023 , Edited by admin on Fri Dec 15 16:35:09 GMT 2023
PRIMARY
EVMPD
SUB10358MIG
Created by admin on Fri Dec 15 16:35:09 GMT 2023 , Edited by admin on Fri Dec 15 16:35:09 GMT 2023
PRIMARY
CHEBI
47657
Created by admin on Fri Dec 15 16:35:09 GMT 2023 , Edited by admin on Fri Dec 15 16:35:09 GMT 2023
PRIMARY
DAILYMED
0P6C6ZOP5U
Created by admin on Fri Dec 15 16:35:09 GMT 2023 , Edited by admin on Fri Dec 15 16:35:09 GMT 2023
PRIMARY
PUBCHEM
449193
Created by admin on Fri Dec 15 16:35:09 GMT 2023 , Edited by admin on Fri Dec 15 16:35:09 GMT 2023
PRIMARY