Roflumilast

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 Search

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
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022522s006lbl.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.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Phosphodiesterase 4 52 Target ID: CHEMBL2093863 Sources: http://ec.europa.eu/health/documents/community-register/2010/2010070580352/anx_80352_en.pdf	Inhibitor 8297		0.8 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Chronic obstructive pulmonary disease 174 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022522s006lbl.pdf	Secondary		Approved 8429	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

C_max

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

T_1/2

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 DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022522s003lbl.pdf			ROFLUMILAST plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
1% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022522s003lbl.pdf			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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf	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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf	Disc. AE: Diarrhea, Nausea... AEs leading to discontinuation/dose reduction: Diarrhea (2.4%) Nausea (1.6%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf
5000 ug single, oral Highest studied dose Dose: 5000 ug Route: oral Route: single Dose: 5000 ug Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf	healthy, adult n = 1 Health Status: healthy Age Group: adult Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf	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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf

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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf	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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf	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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf
Arterial hypotension	1 patient	5000 ug single, oral Highest studied dose Dose: 5000 ug Route: oral Route: single Dose: 5000 ug Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf	healthy, adult n = 1 Health Status: healthy Age Group: adult Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf
Clamminess	1 patient	5000 ug single, oral Highest studied dose Dose: 5000 ug Route: oral Route: single Dose: 5000 ug Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf	healthy, adult n = 1 Health Status: healthy Age Group: adult Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf
Dizziness	1 patient	5000 ug single, oral Highest studied dose Dose: 5000 ug Route: oral Route: single Dose: 5000 ug Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf	healthy, adult n = 1 Health Status: healthy Age Group: adult Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf
Gastrointestinal disorders	1 patient	5000 ug single, oral Highest studied dose Dose: 5000 ug Route: oral Route: single Dose: 5000 ug Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf	healthy, adult n = 1 Health Status: healthy Age Group: adult Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf
Headache	1 patient	5000 ug single, oral Highest studied dose Dose: 5000 ug Route: oral Route: single Dose: 5000 ug Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf	healthy, adult n = 1 Health Status: healthy Age Group: adult Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf
Lightheadedness	1 patient	5000 ug single, oral Highest studied dose Dose: 5000 ug Route: oral Route: single Dose: 5000 ug Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf	healthy, adult n = 1 Health Status: healthy Age Group: adult Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf
Palpitations	1 patient	5000 ug single, oral Highest studied dose Dose: 5000 ug Route: oral Route: single Dose: 5000 ug Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf	healthy, adult n = 1 Health Status: healthy Age Group: adult Population Size: 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737	inhibitor 1767 inducer 389 substrate 1037	inhibitor 1852 substrate 1217	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2A6 707 CYP2B6 810 CYP2C8 911 CYP2C19 1478 CYP2E1 882 CYP3A4/5 278 CYP4A9/11 37 P-gp 1461	CYP1A2 1054 P-gp 1537 CYP1A1 349 CYP2A6 543 CYP2B6 664 CYP2C8 693 CYP2C19 991 CYP2E1 667 CYP3A5 395	CYP1A2 701 CYP2A6 79 CYP2C19 293 CYP3A4/5 124 CYP2B6 547 CYP2B1/2 1 CYP3A1/2 3 CYP4A1 17 CYP4A3 5

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP2A6 739	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP2B1/2 4	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 54.0	no
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP2C19 1553	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP3A1/2 4	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 54.0	no
CYP3A4/5 335	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP3A4/5 335	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP4A1 25	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 54.0	no
CYP4A3 5	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 54.0	no
CYP4A9/11 37	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000SumR.pdf Page: 4.0	no
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	weak

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP1A2 1054	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf 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% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 3.0
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf 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% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 3.0
CYP1A1 349	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 52.0	no
CYP2A6 543	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 52.0	no
CYP2B6 664	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 52.0	no
CYP2C19 991	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 52.0	no
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 52.0	no
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 52.0	no
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 52.0	no
CYP2E1 667	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 52.0	no
CYP3A5 395	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 52.0	no
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000SumR.pdf Page: 5.0	no

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000OtherR.pdf Page: 81.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:47657	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:47657
ChemicalBook	CB7412688	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB7412688
MolPort	MolPort-006-069-128	https://www.molport.com/shop/molecule-link/MolPort-006-069-128
Selleck Chemicals	Roflumilast(Daxas)	http://www.selleckchem.com/products/Roflumilast(Daxas).html
ZINC	ZINC000000592419	http://zinc15.docking.org/substances/ZINC000000592419
eMolecules	6760347	https://www.emolecules.com/cgi-bin/more?vid=6760347

PubMed

Title	Date	PubMed
		252160944
Dynamic activation of cystic fibrosis transmembrane conductance regulator by type 3 and type 4D phosphodiesterase inhibitors.	2005 Aug	15901792
Treating COPD with PDE 4 inhibitors.	2007	18268925
Quinolines as a novel structural class of potent and selective PDE4 inhibitors: optimisation for oral administration.	2009 Mar 1	19195882
[Pharmacological profile of roflumilast].	2010 Dec	21316552
Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease.	2011 May 11	21563134
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	23280750
Roflumilast inhibits the release of chemokines and TNF-α from human lung macrophages stimulated with lipopolysaccharide.	2012 Mar	21913898
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	23871879

Patents

Sample Use Guides

In Vivo Use Guide

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

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

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