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=CC=C(C=C1OCC2CC2)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 54 Target ID: CHEMBL2093863 Sources: http://ec.europa.eu/health/documents/community-register/2010/2010070580352/anx_80352_en.pdf	Inhibitor 8504		0.8 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Chronic obstructive pulmonary disease 175 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022522s006lbl.pdf	Secondary		Approved 8583	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
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
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

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) Health Status: unhealthy Age Group: 64 years (range: 40-91 years) Sex: M+F 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 Health Status: healthy Age Group: adult 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) Health Status: unhealthy Age Group: 64 years (range: 40-91 years) Sex: M+F 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) Health Status: unhealthy Age Group: 64 years (range: 40-91 years) Sex: M+F 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 Health Status: healthy Age Group: adult 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 Health Status: healthy Age Group: adult 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 Health Status: healthy Age Group: adult 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 Health Status: healthy Age Group: adult 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 Health Status: healthy Age Group: adult 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 Health Status: healthy Age Group: adult 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 Health Status: healthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946	inhibitor 2438 inducer 440 substrate 1193	inhibitor 2507 substrate 1388	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 2153 CYP2A6 879 CYP2B6 926 CYP2C8 1057 CYP2C19 2057 CYP2E1 1060 CYP3A4/5 296 CYP4A9/11 35 P-gp 1741	CYP1A2 1197 P-gp 2052 CYP1A1 389 CYP2A6 626 CYP2B6 776 CYP2C8 810 CYP2C19 1119 CYP2E1 729 CYP3A5 446	CYP1A2 832 CYP2A6 86 CYP2C19 329 CYP3A4/5 133 CYP2B6 669 CYP2B1/2 1 CYP3A1/2 3 CYP4A1 17 CYP4A3 6

Drug as perpetrator

Target	Modality	Activity
CYP1A2 2333	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP1A2 2333	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP2A6 911	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP2A6 911	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP2B1/2 4	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 54.0	no
CYP2B6 1160	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP2C19 2141	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP2C19 2141	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP2C8 1117	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP2C9 2497	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP2E1 1146	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP3A1/2 4	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 54.0	no
CYP3A4/5 357	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP3A4/5 357	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
CYP4A1 25	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 54.0	no
CYP4A3 6	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 54.0	no
CYP4A9/11 35	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf Page: 6.0	no
P-gp 1932	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000SumR.pdf Page: 4.0	no
CYP2B6 1160	inducer 1966 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 1197	substrate 4014 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 1946	substrate 4014 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 389	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 52.0	no
CYP2A6 626	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 52.0	no
CYP2B6 776	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 52.0	no
CYP2C19 1119	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 52.0	no
CYP2C8 810	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 52.0	no
CYP2C9 1193	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 52.0	no
CYP2D6 1388	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 52.0	no
CYP2E1 729	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 52.0	no
CYP3A5 446	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000ClinPharmR.pdf Page: 52.0	no
P-gp 2052	substrate 4014 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 2263	inhibitor 2237 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
eMolecules	6760347	https://www.emolecules.com/cgi-bin/more?vid=6760347
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

PubMed

Title	Date	PubMed
		252160944
Effects of roflumilast, a phosphodiesterase-4 inhibitor, on hypoxia- and monocrotaline-induced pulmonary hypertension in rats.	2009 Jul	19386793
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

DALIRESP

Preferred Name

English

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

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