Roflumilast

Summary

Roflumilast (CHEMBL193240) is an approved small-molecule phosphodiesterase IV inhibitor (ATC R03DX07) targeting PDE4B; indicated across 25 conditions including chronic obstructive pulmonary disease and obstructive lung disease; with CIViC clinical evidence for 1 variant-indication association (e.g. STK11 Loss in pancreatic ductal adenocarcinoma).

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: R03DX07 (+1 more)
• Targets: 1 (PDE4B)
• Indications: 25 conditions
• Clinical trials: 110
• Precision-oncology evidence (CIViC): 1 variant–indication association
• Chemistry: 403.2 Da · C17H14Cl2F2N2O3

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL193240
Name	Roflumilast
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	449193
ChEBI	CHEBI:47657
ATC	R03DX07, D05AX06
Molecular formula	C17H14Cl2F2N2O3
Molecular weight	403.2
InChIKey	MNDBXUUTURYVHR-UHFFFAOYSA-N

SMILES: C1CC1COC2=C(C=CC(=C2)C(=O)NC3=C(C=NC=C3Cl)Cl)OC(F)F

IUPAC name: 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)benzamide

ChEBI definition: A benzamide obtained by formal condensation of the carboxy group of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid with the amino group of 3,5-dichloropyridin-4-amine. Used for treatment of bronchial asthma and chronic obstructive pulmonary disease.

Pharmacological roles (ChEBI): phosphodiesterase IV inhibitor, anti-asthmatic drug.

Also known as: Arq-151, ARQ-154 (ROFLUMILAST FOAM), BY-217, BY217, BYK-20869, BYK20869, Daliresp, Daxas, Libertek, Roflumilast, Zoryve, ROFLUMILAST

Patent coverage: 4,647 distinct patent families (19,604 SureChEMBL compound mentions), from 3 matched compound structure(s). One matched structure accounts for 19,088 (97%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).

Gene	Target	Action	pAffinity	Cancer dependency	UniProt
PDE4B	phosphodiesterase 4B	Inhibition	9.4	0.2%	Q07343

Broader ChEMBL bioactivity targets: 7 (assay-derived). Sample: Phosphodiesterase 4, 3’,5’-cyclic-AMP phosphodiesterase 4A, 3’,5’-cyclic-AMP phosphodiesterase 4B, 3’,5’-cyclic-AMP phosphodiesterase 4D, 3’,5’-cyclic-AMP phosphodiesterase 4C, Synaptic vesicular amine transporter, Bile salt export pump.

Bioactivity

ChEMBL activities: 67 potent at pChembl ≥ 5 of 68 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
PDE4D	9.89	IC50	0.13	nM	CHEMBL_ACT_22788678
PDE4B	9.82	IC50	0.15	nM	CHEMBL_ACT_22788676
PDE4D	9.7	IC50	0.2	nM	CHEMBL_ACT_19221607
PDE4B	9.7	IC50	0.2	nM	CHEMBL_ACT_22838526
PDE4A	9.68	IC50	0.21	nM	CHEMBL_ACT_22788563
PDE4D	9.57	IC50	0.27	nM	CHEMBL_ACT_6361379
PDE4D	9.52	IC50	0.3	nM	CHEMBL_ACT_25011021
PDE4A	9.52	IC50	0.3	nM	CHEMBL_ACT_2608060
PDE4A	9.46	IC50	0.35	nM	CHEMBL_ACT_13366559
PDE4D	9.41	IC50	0.39	nM	CHEMBL_ACT_26196247
PDE4B	9.4	IC50	0.4	nM	CHEMBL_ACT_15104179
PDE4B	9.4	Ki	0.4	nM	CHEMBL_ACT_18476977
PDE4D	9.4	IC50	0.4	nM	CHEMBL_ACT_19233920
PDE4D	9.4	IC50	0.4	nM	CHEMBL_ACT_19263186
PDE4B	9.4	IC50	0.4	nM	CHEMBL_ACT_2268979
PDE4D	9.4	IC50	0.4	nM	CHEMBL_ACT_24896948
PDE4D	9.4	IC50	0.4	nM	CHEMBL_ACT_25527386
PDE4D	9.4	IC50	0.4	nM	CHEMBL_ACT_29201685
PDE4D	9.4	IC50	0.4	nM	CHEMBL_ACT_29243151
PDE4D	9.4	IC50	0.4	nM	CHEMBL_ACT_29304864
PDE4B	9.4	IC50	0.4	nM	CHEMBL_ACT_3022672
PDE4B	9.31	IC50	0.49	nM	CHEMBL_ACT_13321386
PDE4B	9.31	IC50	0.49	nM	CHEMBL_ACT_13500174
PDE4A	9.3	IC50	0.5	nM	CHEMBL_ACT_22431018
PDE4D	9.3	AC50	0.5	nM	CHEMBL_ACT_25185670
PDE4D	9.25	IC50	0.56	nM	CHEMBL_ACT_18541818
PDE4A	9.23	IC50	0.59	nM	CHEMBL_ACT_6361362
PDE4D	9.17	IC50	0.68	nM	CHEMBL_ACT_19334647
PDE4D	9.17	IC50	0.68	nM	CHEMBL_ACT_19400649
PDE4D	9.17	IC50	0.68	nM	CHEMBL_ACT_22875452

Target pathways

Aggregated over 1 target gene(s): PDE4B.

Top Reactome pathways

1 total, by targets touching each:

Pathway	Targets	Genes
DARPP-32 events	1	PDE4B

Dominant GO biological processes

GO term	Targets
neutrophil homeostasis	1
cAMP catabolic process	1
neutrophil chemotaxis	1
positive regulation of type II interferon production	1
positive regulation of interleukin-2 production	1
T cell receptor signaling pathway	1
leukocyte migration	1
cellular response to lipopolysaccharide	1
cellular response to xenobiotic stimulus	1
cellular response to epinephrine stimulus	1
negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway	1
regulation of cardiac muscle cell contraction	1
negative regulation of cAMP/PKA signal transduction	1
negative regulation of relaxation of cardiac muscle	1
regulation of calcium ion transmembrane transport via high voltage-gated calcium channel	1

Indications & clinical

Indications

25 indications (4 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).

Indication	Trial phase	MONDO	EFO
chronic obstructive pulmonary disease	4	MONDO:0005002	EFO:0000341
obstructive lung disease	4	MONDO:0002267	HP:0006536
psoriasis	4	MONDO:0005083	EFO:0000676
chronic bronchitis	4	MONDO:0005607	EFO:0006505
bronchiectasis	3	MONDO:0004822	HP:0002110
atopic eczema	3	MONDO:0004980	EFO:0000274
diabetic kidney disease	3	MONDO:0005016	EFO:0000401
asthma	3	MONDO:0004979	MONDO:0004979
metabolic dysfunction-associated steatotic liver disease	2	MONDO:0013209	EFO:0003095
dementia	2	MONDO:0001627	HP:0000726
dermatitis	2	MONDO:0002406	MONDO:0002406
adult acute respiratory distress syndrome	2	MONDO:0100130	MONDO:0100130
rosacea	2	MONDO:0006604	EFO:1000760
type 2 diabetes mellitus	2	MONDO:0005148	MONDO:0005148
fragile X syndrome	2	MONDO:0010383	MONDO:0010383
seborrheic dermatitis	2	MONDO:0006608	EFO:1000764
obesity disorder	1	MONDO:0011122	EFO:0001073
lymphoma	1	MONDO:0005062	EFO:0000574
nervous system disorder	1	MONDO:0005071	EFO:0000618
major depressive disorder	1	MONDO:0002009	MONDO:0002009
peripheral neuropathy	1	MONDO:0005244	EFO:0003100
brain disorder	1	MONDO:0005560	EFO:0005774
neoplasm	0	MONDO:0005070	MONDO:0004992

2 further indication records had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.

Clinical trials

Total trials: 110.

Phase distribution

Phase	Trials
PHASE2	33
PHASE3	32
PHASE4	17
PHASE1	12
Not specified	6
PHASE1/PHASE2	4
PHASE2/PHASE3	3
EARLY_PHASE1	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06440473	PHASE4	RECRUITING	Visualization of Topical Zoryve vs. Vehicle Using Line Field Optical Coherence Tomography in Healthy Skin
NCT07352566	PHASE4	NOT_YET_RECRUITING	Utilization of a Microdevice for Psoriasis and Atopic Dermatitis
NCT01329029	PHASE4	COMPLETED	Roflumilast in Chronic Obstructive Pulmonary Disease (COPD) Patients Treated With Fixed Combinations of Long-acting β2-agonists (LABA) and Inhaled Glucocorticosteroid (ICS)
NCT01443845	PHASE4	COMPLETED	Roflumilast in Chronic Obstructive Pulmonary Disease (COPD) Patients Treated With Fixed Dose Combinations of Long-acting β2-agonist (LABA) and Inhaled Corticosteroid (ICS)
NCT01480661	PHASE4	COMPLETED	Evaluation With CT Scan of Possible Changes in Airways After Treatment With Daxas® in Severe Chronic Obstructive Pulmonary Disease Patients
NCT01595750	PHASE4	UNKNOWN	Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effect of Roflumilast on Endothelial Function in Patients With Chronic Obstructive Pulmonary Disease
NCT01630200	PHASE4	COMPLETED	Effects of ROFLUMILAST on Subclinical Atherosclerosis in Chronic Obstructive Pulmonary Disease (COPD)
NCT01745848	PHASE4	COMPLETED	Roflumilast on Markers of Bone Metabolism and Endothelial Function in COPD
NCT01830959	PHASE4	UNKNOWN	Use of Roflumilast to Prevent Exacerbations in Fibrotic Sarcoidosis Patients (REFS)
NCT01849341	PHASE4	COMPLETED	Roflumilast Safety Administered Once a Day on Alternate Days for Two Weeks Compared to the Usual Dosage Once Daily
NCT02037672	PHASE4	COMPLETED	PDE-4 Inhibitor Roflumilast and Polycystic Ovary Syndrome
NCT02187250	PHASE4	COMPLETED	PDE-4 Inhibitor Roflumilast and GLP-1 Agonist Liraglutide in Polycystic Ovary Syndrome
NCT03073798	PHASE4	COMPLETED	The Effectiveness of Roflumilast in Improving Mucociliary Clearance in Patients With COPD and Chronic Bronchitis
NCT04069312	PHASE4	COMPLETED	Roflumilast or Azithromycin to Prevent COPD Exacerbations (RELIANCE)
NCT05682859	PHASE4	UNKNOWN	Treatment of Chronic Hand Eczema With Oral Roflumilast (HERO)
NCT05684484	PHASE4	COMPLETED	Role of Roflumilast in Ulcerative Colitis
NCT07174011	PHASE4	COMPLETED	Evaluation of the Efficacy and Safety of Oral Roflumilast Versus Intralesional Corticosteroids Injection (ILCs) in the Treatment of Alopecia Areata
NCT06860958	PHASE3	RECRUITING	Roflumilast as an Adjunct to Antidepressants in Major Depressive Disorder Patients
NCT00062582	PHASE3	COMPLETED	Effect of Roflumilast on Pulmonary Function and Respiratory Symptoms in Patients With Chronic Obstructive Pulmonary Disease (COPD) (BY217/M2-110)
NCT00073177	PHASE3	COMPLETED	Efficacy and Safety of Roflumilast in Patients With Asthma (BY217/M2-012)
NCT00076076	PHASE3	COMPLETED	The FLASH Study: A Study of Roflumilast Versus Placebo in Patients With Asthma (BY217/M2-023)
NCT00076089	PHASE3	COMPLETED	OPUS Study: Effect of Roflumilast on Exacerbation Rate in Patients With Chronic Obstructive Pulmonary Disease (BY217/M2-111)
NCT00108823	PHASE3	COMPLETED	The HERO-study: Effects of Roflumilast in Patients With COPD (Chronic Obstructive Pulmonary Disease) (BY217/M2-121)
NCT00163475	PHASE3	COMPLETED	Efficacy and Safety of Roflumilast Taken in the Morning or Evening in Patients With Stable Asthma (12 to 70 y) (BY217/M2-015)
NCT00163527	PHASE3	COMPLETED	Efficacy and Safety of Oral Roflumilast Taken With Low Dose Inhaled Corticosteroids in Patients With Asthma (12 to 70 y) (BY217/M2-013)
NCT00242294	PHASE2/PHASE3	COMPLETED	Efficacy and Safety of Roflumilast in Japanese Patients Older Than 40 Years With Chronic Obstructive Pulmonary Disease (APTA-2217-06)
NCT00242307	PHASE2/PHASE3	COMPLETED	Efficacy and Safety of Roflumilast in Japanese Patients With Bronchial Asthma (20 to 70 y) (APTA-2217-05)
NCT00242320	PHASE3	COMPLETED	Efficacy and Safety of Oral Roflumilast Taken Once Daily in Patients Older Than 40 Years With Chronic Obstructive Pulmonary Disease (BY217/M2-119)
NCT00246922	PHASE3	COMPLETED	Long-term Study of Safety and Efficacy of Roflumilast in Japanese Patients With Bronchial Asthma (20 to 71 y) (APTA-2217-07)
NCT00246935	PHASE3	COMPLETED	Long-term Study of Safety and Efficacy of Roflumilast in Japanese Patients Older Than 40 Years With Chronic Obstructive Pulmonary Disease (APTA-2217-08)
NCT00297102	PHASE3	COMPLETED	Effect of Roflumilast on Exacerbation Rate in Patients With Chronic Obstructive Pulmonary Disease (COPD): The AURA Study (BY217/M2-124)
NCT00297115	PHASE3	COMPLETED	Effect of Roflumilast on Exacerbation Rate in Patients With Chronic Obstructive Pulmonary Disease (COPD): The HERMES Study (BY217/M2-125)
NCT00313209	PHASE3	COMPLETED	Effect of Roflumilast on Lung Function in Chronic Obstructive Pulmonary Disease (COPD) Patients Treated With Salmeterol: The EOS Study (BY217/M2-127)
NCT00424268	PHASE3	COMPLETED	Effect of Roflumilast in Chronic Obstructive Pulmonary Disease (COPD) Patients Treated With Tiotropium: The HELIOS Study (BY217/M2-128)
NCT00430729	PHASE3	COMPLETED	Effect of Roflumilast on Exacerbation Rate in Patients With Chronic Obstructive Pulmonary Disease. Ratio-Study. (BY217/M2-112)
NCT01313494	PHASE3	COMPLETED	A Chronic Obstructive Pulmonary Disease (COPD) Trial Investigating Roflumilast on Safety and Effectiveness in China, Hong Kong and Singapore:
NCT01509677	PHASE3	COMPLETED	Trial to Assess the Anti-inflammatory Effects of Roflumilast in Chronic Obstructive Pulmonary Disease
NCT01973998	PHASE3	COMPLETED	Effects of Roflumilast in Hospitalized Chronic Obstructive Pulmonary Disease( COPD) on Mortality and Re-hospitalization
NCT02165826	PHASE3	COMPLETED	Evaluation of Tolerability and Pharmacokinetics of Roflumilast, 250μg and 500μg, as add-on to Standard COPD Treatment to Treat Severe COPD
NCT02340520	PHASE3	COMPLETED	Enhancement of Corticosteroid Efficacy in COPD

Clinical evidence (CIViC)

Variant × indication × effect (1 predictive associations from 1 curated evidence items):

Variant	Indication	Effect	Therapy	Level	CIViC
STK11 Loss	Pancreatic Ductal Adenocarcinoma	Sensitivity/Response	Roflumilast	CIViC D	EID12555

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline, but PharmGKB curates 0 clinical and 1 variant annotation(s) for this drug (gene-keyed; see PharmGKB).

Related molecules

Related molecules

Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.

50 molecules share ≥1 primary target. Top 50 by shared-target count:

Molecule	Source	Status	Shared targets
TADALAFIL	ChEMBL + PubChem	Phase 4 (approved)	PDE4B
APREMILAST	ChEMBL	Phase 4 (approved)	PDE4B
CRISABOROLE	ChEMBL	Phase 4 (approved)	PDE4B
DIPYRIDAMOLE	ChEMBL	Phase 4 (approved)	PDE4B
ENOXIMONE	ChEMBL	Phase 4 (approved)	PDE4B
ENSIFENTRINE	ChEMBL	Phase 4 (approved)	PDE4B
IBUDILAST	ChEMBL	Phase 4 (approved)	PDE4B
INAMRINONE	ChEMBL	Phase 4 (approved)	PDE4B
LOSARTAN	ChEMBL	Phase 4 (approved)	PDE4B
MILRINONE	ChEMBL	Phase 4 (approved)	PDE4B
PENTOXIFYLLINE	ChEMBL	Phase 4 (approved)	PDE4B
SILDENAFIL	ChEMBL	Phase 4 (approved)	PDE4B
THEOPHYLLINE	ChEMBL	Phase 4 (approved)	PDE4B
VARDENAFIL	ChEMBL	Phase 4 (approved)	PDE4B
CILOMILAST	ChEMBL	Phase 3	PDE4B
MUFEMILAST	ChEMBL	Phase 3	PDE4B
PAPAVERINE	ChEMBL	Phase 3	PDE4B
TETOMILAST	ChEMBL	Phase 3	PDE4B
ZATOLMILAST	ChEMBL	Phase 3	PDE4B
ADIBENDAN	ChEMBL	Phase 2	PDE4B
AZD-6482	ChEMBL	Phase 2	PDE4B
BMS-911543	ChEMBL	Phase 2	PDE4B
CARTAZOLATE	ChEMBL	Phase 2	PDE4B
CDC-801	ChEMBL	Phase 2	PDE4B
CIPAMFYLLINE	ChEMBL	Phase 2	PDE4B
DAXALIPRAM	ChEMBL	Phase 2	PDE4B
DENBUFYLLINE	ChEMBL	Phase 2	PDE4B
ENPROFYLLINE	ChEMBL	Phase 2	PDE4B
FILAMINAST	ChEMBL	Phase 2	PDE4B
IDREBORMILAST	ChEMBL	Phase 2	PDE4B
IMAZODAN	ChEMBL	Phase 2	PDE4B
INDOLIDAN	ChEMBL	Phase 2	PDE4B
LIXAZINONE	ChEMBL	Phase 2	PDE4B
LOTAMILAST	ChEMBL	Phase 2	PDE4B
MK-0873	ChEMBL	Phase 2	PDE4B
NITRAQUAZONE	ChEMBL	Phase 2	PDE4B
ORISMILAST	ChEMBL	Phase 2	PDE4B
PELRINONE	ChEMBL	Phase 2	PDE4B
PICLAMILAST	ChEMBL	Phase 2	PDE4B
PUMAFENTRINE	ChEMBL	Phase 2	PDE4B
REVAMILAST	ChEMBL	Phase 2	PDE4B
ROLIPRAM	ChEMBL	Phase 2	PDE4B
STREPTONIGRIN	ChEMBL	Phase 2	PDE4B
TOCLADESINE	ChEMBL	Phase 2	PDE4B
TOFIMILAST	ChEMBL	Phase 2	PDE4B
TRANIMILAST	ChEMBL	Phase 2	PDE4B
TREQUINSIN	ChEMBL	Phase 2	PDE4B
UK-500001	ChEMBL	Phase 2	PDE4B
ZAPRINAST	ChEMBL	Phase 2	PDE4B
ZARDAVERINE	ChEMBL	Phase 2	PDE4B