Identification

Name
Roflumilast
Accession Number
DB01656  (EXPT02802)
Type
Small Molecule
Groups
Approved
Description

Roflumilast is a phosphodiesterase-4 (PDE-4) inhibitor. Due to its selective inhibition of the PDE4 isoenzyme in lung cells, roflumilast is indicated for the management of chronic obstrtuctive pulmonary disease (COPD) exacerbations. Treatment with Roflumilast is associated with an increase in psychiatric adverse reactions, including suicide and suicidal attempts.

Structure
Thumb
Synonyms
  • ROF
  • roflumilast
  • Roflumilastum
External IDs
B-9302-107 / BY-217 / BY217 / BYK-20869 / BYK20869
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DalirespTablet250 ug/1OralAstra Zeneca Lp2015-07-01Not applicableUs
DalirespTablet500 ug/1OralAllergan2011-02-282016-07-31Us
DalirespTablet500 ug/1OralAstra Zeneca Lp2015-07-01Not applicableUs0310 009520180913 8702 k8pt9a
DalirespTablet500 ug/1OralCardinal Health2011-02-28Not applicableUs
DaxasTablet, film coated500 μgOralAstra Zeneca Ab2010-07-05Not applicableEu
DaxasTablet, film coated500 μgOralAstra Zeneca Ab2010-07-05Not applicableEu
DaxasTablet, film coated500 μgOralAstra Zeneca Ab2010-07-05Not applicableEu
DaxasTablet, film coated500 μgOralAstra Zeneca Ab2010-07-05Not applicableEu
DaxasTablet500 mcgOralAstra Zeneca2010-12-30Not applicableCanada
DaxasTablet, film coated500 μgOralAstra Zeneca Ab2010-07-05Not applicableEu
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
RoflumilastTablet500 ug/1OralTorrent Pharmaceuticals Limited2016-03-01Not applicableUs
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
LibertekRoflumilast (500 μg)Tablet, film coatedOralAstra Zeneca Ab2011-02-282018-02-08Eu
LibertekRoflumilast (500 μg)Tablet, film coatedOralAstra Zeneca Ab2011-02-282018-02-08Eu
LibertekRoflumilast (500 μg)Tablet, film coatedOralAstra Zeneca Ab2011-02-282018-02-08Eu
International/Other Brands
Daliresp
Categories
UNII
0P6C6ZOP5U
CAS number
162401-32-3
Weight
Average: 403.207
Monoisotopic: 402.034954148
Chemical Formula
C17H14Cl2F2N2O3
InChI Key
MNDBXUUTURYVHR-UHFFFAOYSA-N
InChI
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)
IUPAC Name
3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide
SMILES
FC(F)OC1=C(OCC2CC2)C=C(C=C1)C(=O)NC1=C(Cl)C=NC=C1Cl

Pharmacology

Indication

Roflumilast is 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. Roflumilast is not a bronchodilator and is not indicated for the relief of acute bronchospasm.

Associated Conditions
Pharmacodynamics

Roflumilast (and its active metabolite, roflumilast N-oxide) increases cyclic adenosine-3′, 5′-monophosphate (cAMP) in lung cells by inhibiting PDE4. Increased cAMP activates PKA, which inactivates transcription factors involved in inflammation. Romflumilast also decreases the amount of sputum neutrophils and eosinophils in COPD patients.

Mechanism of action

Roflumilast is a phosphodiesterase-4 (PDE-4) inhibitor which, due to its selective inhibition of the PDE4 isoenzyme, has potential antiinflammatory and antimodulatory effects in the pulmonary system. It is thought that the increased levels of intracellular cyclic AMP are responsible for the therapeutic actions of Roflumilast.

TargetActionsOrganism
UcAMP-specific 3',5'-cyclic phosphodiesterase 4D
inhibitor
Human
UcAMP-specific 3',5'-cyclic phosphodiesterase 4A
inhibitor
Human
UcAMP-specific 3',5'-cyclic phosphodiesterase 4B
inhibitor
Human
UcAMP-specific 3',5'-cyclic phosphodiesterase 4C
inhibitor
Human
Absorption

After a 500mcg dose, the bioavailability of roflumilast is about 80%. In the fasted state, maximum plasma concentrations are reached in 0.5 to 2 hours. While in the fed state, Cmax is reduced by 40%, Tmax is increased by one hour, and total absorption is unchanged.

Volume of distribution

Roflumilast has a Vd of 2.9L/kg with a dose of 500mcg. Permeability of roflumilast across the blood-brain barrier appears to be poor in rat studies.

Protein binding

Roflumilast is 99% plasma protein bound.

Metabolism

Roflumilast is metabolized to roflumilast N-oxide, the active metabolite of roflumilast in humans, by CYP3A4 and CYP1A2.

Route of elimination

Roflumilast is excreted 70% in the urine as roflumilast N-oxide.

Half life

Plasma half-life of roflumilast is 17 hours and its metabolite is 30 hours (oral dose).

Clearance

~9.6 L/hour.

Toxicity

Headache, weight loss, GI upset, insomnia, and loose stools.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Roflumilast.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Roflumilast.
2-MethoxyethanolRoflumilast may increase the immunosuppressive activities of 2-Methoxyethanol.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Roflumilast.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Roflumilast.
5-androstenedioneThe metabolism of Roflumilast can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Roflumilast can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Roflumilast.
9-(N-methyl-L-isoleucine)-cyclosporin ARoflumilast may increase the immunosuppressive activities of 9-(N-methyl-L-isoleucine)-cyclosporin A.
AbacavirAbacavir may decrease the excretion rate of Roflumilast which could result in a higher serum level.
Food Interactions
Not Available

References

Synthesis Reference

http://en.wikipedia.org/wiki/File:Roflumilast_syn.png

General References
  1. Meyers JA, Taverna J, Chaves J, Makkinje A, Lerner A: Phosphodiesterase 4 inhibitors augment levels of glucocorticoid receptor in B cell chronic lymphocytic leukemia but not in normal circulating hematopoietic cells. Clin Cancer Res. 2007 Aug 15;13(16):4920-7. [PubMed:17699872]
  2. Sanz MJ, Cortijo J, Taha MA, Cerda-Nicolas M, Schatton E, Burgbacher B, Klar J, Tenor H, Schudt C, Issekutz AC, Hatzelmann A, Morcillo EJ: Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability. Br J Pharmacol. 2007 Oct;152(4):481-92. Epub 2007 Aug 20. [PubMed:17704822]
  3. Barone FC, Barton ME, White RF, Legos JJ, Kikkawa H, Shimamura M, Kuratani K, Kinoshita M: Inhibition of phosphodiesterase type 4 decreases stress-induced defecation in rats and mice. Pharmacology. 2008;81(1):11-7. Epub 2007 Aug 28. [PubMed:17726343]
  4. Chong J, Poole P, Leung B, Black PN: Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011 May 11;(5):CD002309. doi: 10.1002/14651858.CD002309.pub3. [PubMed:21563134]
  5. Grootendorst DC, Gauw SA, Verhoosel RM, Sterk PJ, Hospers JJ, Bredenbroker D, Bethke TD, Hiemstra PS, Rabe KF: Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax. 2007 Dec;62(12):1081-7. Epub 2007 Jun 15. [PubMed:17573446]
  6. Thappali SR, Varanasi KV, Veeraraghavan S, Vakkalanka SK, Mukkanti K: Simultaneous quantitation of IC87114, roflumilast and its active metabolite roflumilast N-oxide in plasma by LC-MS/MS: application for a pharmacokinetic study. J Mass Spectrom. 2012 Dec;47(12):1612-9. doi: 10.1002/jms.3103. [PubMed:23280750]
External Links
KEGG Drug
D05744
PubChem Compound
449193
PubChem Substance
175426853
ChemSpider
395793
BindingDB
14774
ChEBI
47657
ChEMBL
CHEMBL193240
PharmGKB
PA165948052
HET
ROF
Drugs.com
Drugs.com Drug Page
Wikipedia
Roflumilast
ATC Codes
R03DX07 — Roflumilast
PDB Entries
1xmu / 1xoq / 3g4l
FDA label
Download (255 KB)
MSDS
Download (569 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingTreatmentAdvanced B-cell Lymphoid Malignancies1
1CompletedOtherHealthy Volunteers1
1CompletedTreatmentAlzheimer's Disease (AD) / Memory Disturbances1
1CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)1
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentSchizophrenic Disorders1
1CompletedTreatmentType 2 Diabetes Mellitus1
1RecruitingTreatmentLymphoma, B-Cell1
1, 2CompletedTreatmentBMI >30 kg/m21
1, 2CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)1
2Active Not RecruitingTreatmentChronic Obstructive Pulmonary Disease and Allied Conditions1
2CompletedBasic ScienceDementias1
2CompletedTreatmentAsthma Bronchial1
2CompletedTreatmentAsthma, Allergic1
2CompletedTreatmentAtopic Dermatitis (AD)1
2CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)1
2CompletedTreatmentType 2 Diabetes Mellitus1
2RecruitingTreatmentAsthma Bronchial / BMI >30 kg/m21
2RecruitingTreatmentChronic Obstructive Pulmonary Disease (COPD)1
2RecruitingTreatmentNon-Cystic Fibrosis Bronchiectasis1
2TerminatedTreatmentChronic Obstructive Pulmonary Disease (COPD) / Metabolic Syndromes1
2TerminatedTreatmentChronic Obstructive Pulmonary Disease With (Acute) Exacerbation1
2TerminatedTreatmentNonalcoholic Steatohapatitis1
2TerminatedTreatmentPulmonary Disease, Chronic Obstructive1
2Unknown StatusTreatmentSymptomatic Bronchiectasis1
2WithdrawnTreatmentPsoriasis Vulgaris (Plaque Psoriasis)1
2WithdrawnTreatmentSkin Inflammation1
2, 3CompletedTreatmentBronchial Asthma1
2, 3CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)1
3CompletedTreatmentAsthma Bronchial4
3CompletedTreatmentBronchial Asthma1
3CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)15
4Active Not RecruitingTreatmentChronic Obstructive Pulmonary Disease (COPD)1
4Active Not RecruitingTreatmentSarcoidosis1
4CompletedNot AvailablePulmonary Disease, Chronic Obstructive1
4CompletedTreatmentAcute Exacerbation of Chronic Obstructive Pulmonary Disease / Chronic Lung Diseases / Chronic Obstructive Pulmonary Disease (COPD) / Pulmonary Diseases / Respiratory Disorders1
4CompletedTreatmentBMI >30 kg/m2 / Polycystic Ovarian Syndrome2
4CompletedTreatmentChronic Bronchitis / Chronic Obstructive Pulmonary Disease (COPD) / Emphysema1
4CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)1
4Unknown StatusTreatmentChronic Obstructive Pulmonary Disease (COPD)2
Not AvailableCompletedNot AvailableChronic Obstructive Pulmonary Disease (COPD)2
Not AvailableCompletedNot AvailableSevere COPD1
Not AvailableCompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)1
Not AvailableRecruitingNot AvailableAlzheimer's Disease (AD)1
Not AvailableRecruitingNot AvailableChronic Obstructive Pulmonary Disease (COPD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral250 ug/1
TabletOral500 ug/1
TabletOral500 mcg
Tablet, film coatedOral500 μg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8536206No2004-03-082024-03-08Us
US8604064No2004-03-082024-03-08Us
US5712298No2000-01-272020-01-27Us
US8618142No2004-03-082024-03-08Us
US8431154No2003-02-192023-02-19Us
US9468598No2003-02-192023-02-19Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)159.7Not Available
water solubilityinsoluble (0.52-0.56 mg/L at 22°C)Not Available
pKa8.74Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0062 mg/mLALOGPS
logP4.47ALOGPS
logP4.45ChemAxon
logS-4.8ALOGPS
pKa (Strongest Acidic)8.18ChemAxon
pKa (Strongest Basic)2.4ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area60.45 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity93.92 m3·mol-1ChemAxon
Polarizability35.9 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9874
Caco-2 permeable+0.5235
P-glycoprotein substrateNon-substrate0.7295
P-glycoprotein inhibitor INon-inhibitor0.5775
P-glycoprotein inhibitor IINon-inhibitor0.622
Renal organic cation transporterNon-inhibitor0.8057
CYP450 2C9 substrateNon-substrate0.8082
CYP450 2D6 substrateNon-substrate0.7705
CYP450 3A4 substrateSubstrate0.5821
CYP450 1A2 substrateInhibitor0.7732
CYP450 2C9 inhibitorInhibitor0.5686
CYP450 2D6 inhibitorNon-inhibitor0.7204
CYP450 2C19 inhibitorInhibitor0.7813
CYP450 3A4 inhibitorInhibitor0.6242
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8602
Ames testNon AMES toxic0.5216
CarcinogenicityNon-carcinogens0.8843
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.3522 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9704
hERG inhibition (predictor II)Non-inhibitor0.6336
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (81 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0f76-0950700000-9d3dc26457cb82e9e2af

Taxonomy

Description
This compound belongs to the class of organic compounds known as benzamides. These are organic compounds containing a carboxamido substituent attached to a benzene ring.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzoic acids and derivatives
Direct Parent
Benzamides
Alternative Parents
Benzoyl derivatives / Phenol ethers / Phenoxy compounds / Polyhalopyridines / Alkyl aryl ethers / Aryl chlorides / Heteroaromatic compounds / Secondary carboxylic acid amides / Azacyclic compounds / Organopnictogen compounds
show 6 more
Substituents
Benzamide / Phenoxy compound / Benzoyl / Polyhalopyridine / Phenol ether / Alkyl aryl ether / Aryl chloride / Aryl halide / Pyridine / Heteroaromatic compound
show 19 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
organofluorine compound, aromatic ether, benzamides, cyclopropanes, chloropyridine (CHEBI:47657)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Ubiquitin protein ligase binding
Specific Function
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
Gene Name
PDE4D
Uniprot ID
Q08499
Uniprot Name
cAMP-specific 3',5'-cyclic phosphodiesterase 4D
Molecular Weight
91114.1 Da
References
  1. Barone FC, Barton ME, White RF, Legos JJ, Kikkawa H, Shimamura M, Kuratani K, Kinoshita M: Inhibition of phosphodiesterase type 4 decreases stress-induced defecation in rats and mice. Pharmacology. 2008;81(1):11-7. Epub 2007 Aug 28. [PubMed:17726343]
  2. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [PubMed:10592235]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Metal ion binding
Specific Function
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
Gene Name
PDE4A
Uniprot ID
P27815
Uniprot Name
cAMP-specific 3',5'-cyclic phosphodiesterase 4A
Molecular Weight
98142.155 Da
References
  1. Barone FC, Barton ME, White RF, Legos JJ, Kikkawa H, Shimamura M, Kuratani K, Kinoshita M: Inhibition of phosphodiesterase type 4 decreases stress-induced defecation in rats and mice. Pharmacology. 2008;81(1):11-7. Epub 2007 Aug 28. [PubMed:17726343]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Metal ion binding
Specific Function
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in mediating central nervous system effects of therapeutic agents ranging f...
Gene Name
PDE4B
Uniprot ID
Q07343
Uniprot Name
cAMP-specific 3',5'-cyclic phosphodiesterase 4B
Molecular Weight
83342.695 Da
References
  1. Barone FC, Barton ME, White RF, Legos JJ, Kikkawa H, Shimamura M, Kuratani K, Kinoshita M: Inhibition of phosphodiesterase type 4 decreases stress-induced defecation in rats and mice. Pharmacology. 2008;81(1):11-7. Epub 2007 Aug 28. [PubMed:17726343]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Metal ion binding
Specific Function
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
Gene Name
PDE4C
Uniprot ID
Q08493
Uniprot Name
cAMP-specific 3',5'-cyclic phosphodiesterase 4C
Molecular Weight
79900.795 Da
References
  1. Barone FC, Barton ME, White RF, Legos JJ, Kikkawa H, Shimamura M, Kuratani K, Kinoshita M: Inhibition of phosphodiesterase type 4 decreases stress-induced defecation in rats and mice. Pharmacology. 2008;81(1):11-7. Epub 2007 Aug 28. [PubMed:17726343]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Kelly Freeman ML: Clinical Considerations for Roflumilast: A New Treatment for COPD. Consult Pharm. 2012 Mar;27(3):189-93. doi: 10.4140/TCP.n.2012.189. [PubMed:22421519]
  2. Baye J: Roflumilast (daliresp): a novel phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease. P T. 2012 Mar;37(3):149-61. [PubMed:22605906]
  3. Rabe KF: Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharmacol. 2011 May;163(1):53-67. doi: 10.1111/j.1476-5381.2011.01218.x. [PubMed:21232047]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 05:04