Zileuton

Summary

Zileuton (CHEMBL93) is an approved small-molecule EC 1.13.11.34 (arachidonate 5-lipoxygenase) inhibitor targeting ALOX5; indicated across 9 conditions including asthma and chronic obstructive pulmonary disease.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• Targets: 1 (ALOX5)
• Indications: 9 conditions
• Clinical trials: 15
• Chemistry: 236.29 Da · C11H12N2O2S

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL93
Name	Zileuton
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	60490
ChEBI	CHEBI:10112
Molecular formula	C11H12N2O2S
Molecular weight	236.29
InChIKey	MWLSOWXNZPKENC-UHFFFAOYSA-N

SMILES: CC(C1=CC2=CC=CC=C2S1)N(C(=O)N)O

IUPAC name: 1-[1-(1-benzothiophen-2-yl)ethyl]-1-hydroxyurea

ChEBI definition: A member of the class of 1-benzothiophenes that is 1-benzothiophene in which the hydrogen at position 2 is replaced by a 1-[carbamoyl(hydroxy)amino]ethyl group. A selective 5-lipoxygenase inhibitor, it inhibits the formation of leukotrienes LTB4, LTC4, LDT4, and LTE4. It is used for the management of chronic asthma.

Pharmacological roles (ChEBI): EC 1.13.11.34 (arachidonate 5-lipoxygenase) inhibitor, non-steroidal anti-inflammatory drug, anti-asthmatic drug, leukotriene antagonist, ferroptosis inhibitor.

Also known as: A-64077, ABBOTT-64077, NSC-730712, NSC-759277, Zileuton, Zyflo, Zyflo cr, zileuton, SID26719885, SID29215400, ZILEUTON, Zileuton (Racemate)

Patent coverage: 4,994 distinct patent families (21,372 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 21,291 (100%) 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
ALOX5	5-LOX	Inhibition	5.82	0.7%	P09917

Broader ChEMBL bioactivity targets: 14 (assay-derived). Sample: Prelamin-A/C, Polyunsaturated fatty acid 5-lipoxygenase, Protein-lysine 6-oxidase, Prostaglandin G/H synthase 2, Bifunctional epoxide hydrolase 2, Lysosomal alpha-glucosidase, Polyunsaturated fatty acid lipoxygenase ALOX15, Polyunsaturated fatty acid 5-lipoxygenase, Polyunsaturated fatty acid lipoxygenase ALOX12, Leukotriene B4 receptor 1.

Bioactivity

ChEMBL activities: 127 potent at pChembl ≥ 5 of 135 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
P12527	6.85	IC50	140	nM	CHEMBL_ACT_251914
ALOX5	6.82	IC50	150	nM	CHEMBL_ACT_18792994
ALOX5	6.82	IC50	150	nM	CHEMBL_ACT_22956981
ALOX5	6.82	IC50	150	nM	CHEMBL_ACT_29056674
P12527	6.75	IC50	180	nM	CHEMBL_ACT_18720728
P48999	6.72	IC50	190	nM	CHEMBL_ACT_15754985
P12527	6.7	IC50	200	nM	CHEMBL_ACT_578950
LMNA	6.65	Potency	223.9	nM	CHEMBL_ACT_3648766
ALOX5	6.52	IC50	300	nM	CHEMBL_ACT_13908007
ALOX5	6.52	IC50	300	nM	CHEMBL_ACT_25633110
ALOX5	6.5	IC50	320	nM	CHEMBL_ACT_1079003
P12527	6.5	IC50	320	nM	CHEMBL_ACT_418340
ALOX5	6.46	IC50	350	nM	CHEMBL_ACT_18783118
P12527	6.43	IC50	370	nM	CHEMBL_ACT_221598
ALOX5	6.41	IC50	390	nM	CHEMBL_ACT_25022365
ALOX15	6.4	IC50	400	nM	CHEMBL_ACT_18050072
ALOX5	6.4	IC50	400	nM	CHEMBL_ACT_2594356
ALOX5	6.39	IC50	410	nM	CHEMBL_ACT_13488775
LTB4R	6.38	IC50	420	nM	CHEMBL_ACT_828284
ALOX5	6.33	EC50	470	nM	CHEMBL_ACT_717637
ALOX5	6.3	IC50	500	nM	CHEMBL_ACT_10891611
ALOX5	6.3	IC50	500	nM	CHEMBL_ACT_10891647
ALOX5	6.3	IC50	500	nM	CHEMBL_ACT_12086154
ALOX5	6.3	IC50	500	nM	CHEMBL_ACT_12186796
P12527	6.3	IC50	500	nM	CHEMBL_ACT_1238228
ALOX5	6.3	IC50	500	nM	CHEMBL_ACT_19307563
P12527	6.3	IC50	500	nM	CHEMBL_ACT_749562
P12527	6.3	IC50	500	nM	CHEMBL_ACT_804137
ALOX5	6.3	IC50	500	nM	CHEMBL_ACT_8052312
P12527	6.3	IC50	500	nM	CHEMBL_ACT_945300

Target pathways

Aggregated over 1 target gene(s): ALOX5.

Top Reactome pathways

29 total, by targets touching each:

Pathway	Targets	Genes
Cytokine Signaling in Immune system	1	ALOX5
Metabolism	1	ALOX5
Innate Immune System	1	ALOX5
Immune System	1	ALOX5
Synthesis of 5-eicosatetraenoic acids	1	ALOX5
Synthesis of Leukotrienes (LT) and Eoxins (EX)	1	ALOX5
Biosynthesis of Lipoxins (LX)	1	ALOX5
Arachidonate metabolism	1	ALOX5
Interleukin-1 family signaling	1	ALOX5
Signaling by Interleukins	1	ALOX5
Metabolism of lipids	1	ALOX5
Interleukin-4 and Interleukin-13 signaling	1	ALOX5
Neutrophil degranulation	1	ALOX5
Fatty acid metabolism	1	ALOX5
Interleukin-18 signaling	1	ALOX5
Biosynthesis of D-series resolvins	1	ALOX5
Biosynthesis of DHA-derived SPMs	1	ALOX5
Biosynthesis of specialized proresolving mediators (SPMs)	1	ALOX5
Biosynthesis of EPA-derived SPMs	1	ALOX5
Biosynthesis of maresins	1	ALOX5
Biosynthesis of DPA-derived SPMs	1	ALOX5
Biosynthesis of E-series 18(S)-resolvins	1	ALOX5
Biosynthesis of aspirin-triggered D-series resolvins	1	ALOX5
Biosynthesis of E-series 18(R)-resolvins	1	ALOX5
Biosynthesis of DPAn-3 SPMs	1	ALOX5
Biosynthesis of DPAn-3-derived protectins and resolvins	1	ALOX5
Biosynthesis of DPAn-3-derived maresins	1	ALOX5
Biosynthesis of DPAn-3-derived 13-series resolvins	1	ALOX5
Biosynthesis of electrophilic ω-3 PUFA oxo-derivatives	1	ALOX5

Dominant GO biological processes

GO term	Targets
negative regulation of endothelial cell proliferation	1
leukocyte chemotaxis involved in inflammatory response	1
leukocyte migration involved in inflammatory response	1
leukotriene production involved in inflammatory response	1
leukotriene metabolic process	1
humoral immune response	1
negative regulation of angiogenesis	1
arachidonate metabolic process	1
leukotriene biosynthetic process	1
lipoxygenase pathway	1
positive regulation of bone mineralization	1
lipid oxidation	1
dendritic cell migration	1
glucose homeostasis	1
long-chain fatty acid biosynthetic process	1

Indications & clinical

Indications

9 indications (1 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
asthma	4	MONDO:0004979	MONDO:0004979
chronic obstructive pulmonary disease	3	MONDO:0005002	EFO:0000341
nicotine dependence	2	MONDO:0008575	EFO:0003768
idiopathic pulmonary fibrosis	2	MONDO:0800504	EFO:0000768
acne	2	MONDO:0011438	EFO:0003894
lung neoplasm	2	MONDO:0021117	MONDO:0008903
chronic myeloid leukemia	1	MONDO:0011996	EFO:0000339
sickle cell disease	1	MONDO:0011382	MONDO:0011382

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

Clinical trials

Total trials: 15.

Phase distribution

Phase	Trials
PHASE2	7
PHASE1/PHASE2	3
PHASE1	2
PHASE4	1
PHASE3	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00575861	PHASE4	COMPLETED	Zileuton and Exhaled Nitric Oxide in Asthmatics
NCT00493974	PHASE3	TERMINATED	Zileuton to Treat Adults With Chronic Obstructive Pulmonary Disease (The LEUKO Study)
NCT00056004	PHASE2	COMPLETED	Zileuton in Preventing Lung Cancer in Patients With Bronchial Dysplasia
NCT00070486	PHASE2	COMPLETED	Carboplatin and Gemcitabine Combined With Celecoxib and/or Zileuton in Treating Patients With Advanced Non-Small Cell Lung Cancer
NCT00098358	PHASE2	UNKNOWN	Study of Oral Zileuton in the Treatment of Moderate to Severe Facial Acne Vulgaris
NCT00262405	PHASE2	COMPLETED	Zileuton for the Treatment of Idiopathic Pulmonary Fibrosis
NCT00299065	PHASE1/PHASE2	COMPLETED	Safety Study of Zileuton Injection in Patients With Asthma
NCT00467831	PHASE1/PHASE2	TERMINATED	Pilot Study of a Multi-Drug Regimen for Severe Pulmonary Fibrosis in Hermansky-Pudlak Syndrome
NCT00534625	PHASE2	COMPLETED	Assessment of PFT, Safety, and PK of Zileuton Injection in Asthma Patients
NCT00723021	PHASE2	COMPLETED	PF-04191834 Single Dose Bronchodilatory Study In Asthma.
NCT01021215	PHASE1/PHASE2	COMPLETED	Zileuton With or Without Celecoxib As Chemopreventive Agents in Smokers
NCT02348203	PHASE2	COMPLETED	Aspirin and Zileuton and Biomarker Expression in Nasal Tissue of Current Smokers
NCT01130688	PHASE1	TERMINATED	Safety of Zileuton (Zyflo) in Combination With Imatinib Mesylate (Gleevec) in CML.
NCT01136941	PHASE1	COMPLETED	Trial of Zileuton CR in Children and Adults With Sickle Cell Disease
NCT01174056	EARLY_PHASE1	COMPLETED	Evaluation of Rosiglitazone Anti-inflammatory Effect With FDG-PET Imaging

Clinical evidence (CIViC)

No CIViC predictive evidence (expected for non-precision-medicine drugs).

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline, but PharmGKB curates 1 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.

33 molecules share ≥1 primary target. Top 33 by shared-target count:

Molecule	Source	Status	Shared targets
CAPSAICIN	ChEMBL	Phase 4 (approved)	ALOX5
CELECOXIB	ChEMBL	Phase 4 (approved)	ALOX5
CHLOROXINE	ChEMBL	Phase 4 (approved)	ALOX5
HEXYLRESORCINOL	ChEMBL	Phase 4 (approved)	ALOX5
IBUPROFEN	ChEMBL	Phase 4 (approved)	ALOX5
INDOMETHACIN	ChEMBL	Phase 4 (approved)	ALOX5
CAFFEIC ACID	ChEMBL	Phase 3	ALOX5
CURCUMIN	ChEMBL	Phase 3	ALOX5
FIBOFLAPON	ChEMBL	Phase 3	ALOX5
HYDROXYTYROSOL	ChEMBL	Phase 3	ALOX5
QUERCETIN	ChEMBL	Phase 3	ALOX5
RESVERATROL	ChEMBL	Phase 3	ALOX5
VELIFLAPON	ChEMBL	Phase 3	ALOX5
ANTHRALIN	ChEMBL	Phase 2	ALOX5
ATRELEUTON	ChEMBL	Phase 2	ALOX5
DOCEBENONE	ChEMBL	Phase 2	ALOX5
ENOFELAST	ChEMBL	Phase 2	ALOX5
ENOXOLONE	ChEMBL	Phase 2	ALOX5
FENLEUTON	ChEMBL	Phase 2	ALOX5
LICOFELONE	ChEMBL	Phase 2	ALOX5
LUTEOLIN	ChEMBL	Phase 2	ALOX5
MK-7622	ChEMBL	Phase 2	ALOX5
NAFAZATROM	ChEMBL	Phase 2	ALOX5
PIPERINE	ChEMBL	Phase 2	ALOX5
PRIFELONE	ChEMBL	Phase 2	ALOX5
PTEROSTILBENE	ChEMBL	Phase 2	ALOX5
QUIFLAPON	ChEMBL	Phase 2	ALOX5
SETILEUTON	ChEMBL	Phase 2	ALOX5
TAGORIZINE	ChEMBL	Phase 2	ALOX5
TEBUFELONE	ChEMBL	Phase 2	ALOX5
TEPOXALIN	ChEMBL	Phase 2	ALOX5
TOMELUKAST	ChEMBL	Phase 2	ALOX5
XANTHOHUMOL	ChEMBL	Phase 2	ALOX5