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

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

Molecular Formula	C17H14Cl2F2N2O3
Molecular Weight	403.207
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description

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	Inhibitor 8,297		0.8 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Chronic obstructive pulmonary disease 174	Secondary		Approved 8,429	DALIRESP

C_max

Value	Dose	Co-administered	Analyte	Population
12.5 ng/mL	0.5 mg single, oral		ROFLUMILAST plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
65.1 ng × h/mL	0.5 mg single, oral		ROFLUMILAST plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
17 h			ROFLUMILAST plasma	Homo sapiens
19.9 h	0.5 mg single, oral		ROFLUMILAST plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
1%			ROFLUMILAST plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
450 ug 1 times / day steady, oral Recommended	unhealthy, 64 years (range: 40-91 years)	Disc. AE: Diarrhea, Nausea...
5000 ug single, oral Highest studied dose	healthy, adult	Other AEs: Headache, Gastrointestinal disorders...

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AEs

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AE	Significance	Dose	Population
Nausea	1.6% Disc. AE	450 ug 1 times / day steady, oral Recommended	unhealthy, 64 years (range: 40-91 years)
Diarrhea	2.4% Disc. AE	450 ug 1 times / day steady, oral Recommended	unhealthy, 64 years (range: 40-91 years)
Arterial hypotension	1 patient	5000 ug single, oral Highest studied dose	healthy, adult
Clamminess	1 patient	5000 ug single, oral Highest studied dose	healthy, adult
Dizziness	1 patient	5000 ug single, oral Highest studied dose	healthy, adult

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737	inhibitor 1,767 inducer 389 substrate 1,037	inhibitor 1,852 substrate 1,217	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1,524 CYP2A6 707 CYP2B6 810 CYP2C8 911 CYP2C19 1,478 CYP2E1 882 CYP3A4/5 278 CYP4A9/11 37 P-gp 1,461	CYP1A2 1,054 P-gp 1,537 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

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Target	Modality	Activity
CYP1A2 1,692	inducer 1,573	no
CYP1A2 1,692	inhibitor 3,277	no
CYP2A6 739	inducer 1,573	no
CYP2A6 739	inhibitor 3,277	no
CYP2B1/2 4	inducer 1,573	no

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP1A2 1,054	substrate 3,367	major	yes (co-administration study)
CYP3A4 1,737	substrate 3,367	major	yes (co-administration study)
CYP1A1 349	substrate 3,367	no
CYP2A6 543	substrate 3,367	no
CYP2B6 664	substrate 3,367	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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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

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PubMed

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Title	Date	PubMed
		252160944
Phosphodiesterase type 4 inhibitors cause proinflammatory effects in vivo.	2006 Oct	16861399
Phosphodiesterase 4 inhibitors augment levels of glucocorticoid receptor in B cell chronic lymphocytic leukemia but not in normal circulating hematopoietic cells.	2007 Aug 15	17699872
Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD.	2007 Dec	17573446
Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability.	2007 Oct	17704822

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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.

Substance Class	Chemical
Record UNII	0P6C6ZOP5U
Record Status	`Validated (UNII)`
Record Version

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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

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Classification Tree

Code System

Code

Other systemic drugs for obstructive airway diseases

WHO-ATC

R03DX07

Asthma

LIVERTOX

NBK548195

LUNG DISEASES, OBSTRUCTIVE

EMA ASSESSMENT REPORTS

DAXAS (AUTHORIZED: PULMONARY DISEASE, CHRONIC OBSTRUCTIVE )

Other systemic drugs for obstructive airway diseases

WHO-VATC

QR03DX07

Established Pharmacologic Class

NDF-RT

N0000182961

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Code System

Code

Type

Description

NCI_THESAURUS

C76890

PRIMARY

INN

7598

PRIMARY

IUPHAR

6962

PRIMARY

CAS

162401-32-3

PRIMARY

FDA UNII

0P6C6ZOP5U

PRIMARY

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					PUO0521HZV

CYTOCHROME P450 3A4

METABOLIC ENZYME -> SUBSTRATE


					6D53G0FD0Z

PLASMA PROTEIN FRACTION (HUMAN)

BINDER->LIGAND

Amount:

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					651CFC5G66

CAMP-SPECIFIC 3',5'-CYCLIC PHOSPHODIESTERASE 4A

TARGET -> INHIBITOR


					0P6C6ZOP5U

Roflumilast

EXCRETED UNCHANGED

Comments:

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%).

Qualification:

URINE

Amount:

[<1] % (average)


					081I12ZA58

CYTOCHROME P450 2C19

METABOLIC ENZYME -> SUBSTRATE

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					F7AS459SFD

3,5-DICHLOROPYRIDIN-4-AMINE

METABOLITE -> PARENT


					3RXV4ND32V

N-(3,5-DICHLORO-4-PYRIDINYL)-4-(DIFLUOROMETHOXY)-3-HYDROXYBENZAMIDE

METABOLITE -> PARENT


					F08MQ6CZCS

ROFLUMILAST N-OXIDE

METABOLITE ACTIVE -> PARENT

Comments:

The N-oxide accounts for about 90% of the biological action of roflumilast and produces a long-lasting, competitive inhibition of PDE4over a 24-hr period such that roflumilast may be administered once daily.

Interaction Type:

MAJOR

Amount:


					SJ65RQ386K

(2S,3S,4S,5R)-6-(5-((3,5-DICHLORO-4-PYRIDYL)CARBAMOYL)-2-(DIFLUOROMETHOXY)PHENOXY)-3,4,5-TRIHYDROXY-TETRAHYDROPYRAN-2-CARBOXYLIC ACID

METABOLITE -> PARENT


					SD9GLG46RW

(2S,3S,4S,5R)-6-((5-CHLORO-4-((3-(CYCLOPROPYLMETHOXY)-4-(DIFLUOROMETHOXY)BENZOYL)AMINO)-3-PYRIDYL)OXY)-3,4,5-TRIHYDROXY-TETRAHYDROPYRAN-2-CARBOXYLIC ACID

METABOLITE -> PARENT

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					0P6C6ZOP5U

Roflumilast

ACTIVE MOIETY

Amount:

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Name	Property Type	Amount
Tmax	PHARMACOKINETIC	1 hours (average)

Volume of Distribution	PHARMACOKINETIC	2.9 Liters/Kilogram (average)

Biological Half-life	PHARMACOKINETIC	17 hours (average)

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator