Leflunomide

Summary

Leflunomide (CHEMBL960) is an approved small-molecule non-steroidal anti-inflammatory drug (ATC L04AK01) targeting DHODH; indicated across 24 conditions including rheumatoid arthritis and psoriatic arthritis.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: L04AK01
• Targets: 1 (DHODH)
• Indications: 24 conditions
• Clinical trials: 79
• Chemistry: 270.21 Da · C12H9F3N2O2

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL960
Name	Leflunomide
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	3899
ChEBI	CHEBI:6402
ATC	L04AK01
Molecular formula	C12H9F3N2O2
Molecular weight	270.21
InChIKey	VHOGYURTWQBHIL-UHFFFAOYSA-N

SMILES: CC1=C(C=NO1)C(=O)NC2=CC=C(C=C2)C(F)(F)F

IUPAC name: 5-methyl-N-[4-(trifluoromethyl)phenyl]-1,2-oxazole-4-carboxamide

ChEBI definition: A monocarboxylic acid amide obtained by formal condensation of the carboxy group of 5-methyl-1,2-oxazole-4-carboxylic acid with the anilino group of 4-(trifluoromethyl)aniline. The prodrug of teriflunomide.

Pharmacological roles (ChEBI): non-steroidal anti-inflammatory drug, antineoplastic agent, antiparasitic agent, EC 1.3.98.1 [dihydroorotate oxidase (fumarate)] inhibitor, hepatotoxic agent, prodrug, pyrimidine synthesis inhibitor, immunosuppressive agent, EC 3.1.3.16 (phosphoprotein phosphatase) inhibitor, tyrosine kinase inhibitor.

Also known as: Arava, HWA-486, L04AA13, Leflunomida, Leflunomide, Leflunomide medac, Leflunomide ratiopharm, Leflunomide teva, Leflunomide winthrop, NSC-677411, NSC-759864, Repso

Patent coverage: 12,680 distinct patent families (52,218 SureChEMBL compound mentions), from 1 matched compound structure(s). 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
DHODH	dihydroorotate dehydrogenase (quinone)	Inhibition	4.89	33.9%	Q02127

Broader ChEMBL bioactivity targets: 35 (assay-derived). Sample: Nuclear receptor ROR-gamma, Survival motor neuron protein, Prelamin-A/C, RecQ-like DNA helicase BLM, 4’-phosphopantetheinyl transferase ffp, Thrombopoietin, NPC intracellular cholesterol transporter 1, Geminin, Ras-related protein Rab-9A, Peripheral myelin protein 22.

Bioactivity

ChEMBL activities: 36 potent at pChembl ≥ 5 of 64 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
LMNA	8.49	Potency	3.2	nM	CHEMBL_ACT_3663555
Q63707	8.05	IC50	9	nM	CHEMBL_ACT_57173
O35435	7.52	IC50	30	nM	CHEMBL_ACT_57172
CYP1A2	7.2	AC50	63.1	nM	CHEMBL_ACT_6043023
NPSR1	7.1	Potency	79.4	nM	CHEMBL_ACT_4901165
HTT	6.5	Potency	316.2	nM	CHEMBL_ACT_4835294
CYP1A2	6.3	IC50	500	nM	CHEMBL_ACT_7767937
NPC1	6.25	Potency	562.3	nM	CHEMBL_ACT_4752295
CYP3A4	6.2	Potency	631	nM	CHEMBL_ACT_4981437
CYP3A4	6.2	Potency	631	nM	CHEMBL_ACT_5046651
RAB9A	6.14	Potency	730.8	nM	CHEMBL_ACT_3860966
DHODH	6.1	IC50	800	nM	CHEMBL_ACT_23167044
P08659	6.05	Potency	891.3	nM	CHEMBL_ACT_5004919
RAB9A	5.85	Potency	1412	nM	CHEMBL_ACT_3833922
Q63707	5.8	IC50	1600	nM	CHEMBL_ACT_5177293
NPC1	5.74	Potency	1836	nM	CHEMBL_ACT_4732695
SLC6A3	5.64	Ki	2291	nM	CHEMBL_ACT_7767960
SLC6A3	5.54	IC50	2884	nM	CHEMBL_ACT_7767959
GMNN	5.5	Potency	3162	nM	CHEMBL_ACT_5065143
HTR2A	5.43	AC50	3742	nM	CHEMBL_ACT_25173798
SLC6A2	5.34	Ki	4591	nM	CHEMBL_ACT_7767896
SLC6A2	5.33	IC50	4630	nM	CHEMBL_ACT_7767895
CYP3A4	5.3	Potency	5012	nM	CHEMBL_ACT_4949475
CYP3A4	5.3	Potency	5012	nM	CHEMBL_ACT_5078868
CYP3A4	5.3	AC50	5012	nM	CHEMBL_ACT_6027454
HTT	5.25	Potency	5623	nM	CHEMBL_ACT_4855670
SMN1	5.15	Potency	7080	nM	CHEMBL_ACT_4590904
THPO	5.1	Potency	7943	nM	CHEMBL_ACT_4805533
THPO	5.1	Potency	7943	nM	CHEMBL_ACT_5070284
SLC6A2	5.07	AC50	8601	nM	CHEMBL_ACT_25145547

Target pathways

Aggregated over 1 target gene(s): DHODH.

Top Reactome pathways

1 total, by targets touching each:

Pathway	Targets	Genes
Pyrimidine biosynthesis	1	DHODH

Dominant GO biological processes

GO term	Targets
‘de novo’ pyrimidine nucleobase biosynthetic process	1
UDP biosynthetic process	1
pyrimidine ribonucleotide biosynthetic process	1
‘de novo’ UMP biosynthetic process	1
pyrimidine nucleotide biosynthetic process	1
UMP biosynthetic process	1

Indications & clinical

Indications

24 indications (2 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
rheumatoid arthritis	4	MONDO:0008383	EFO:0000685
psoriatic arthritis	4	MONDO:0011849	EFO:0003778
myasthenia gravis	3	MONDO:0009688	EFO:0004991
lupus nephritis	3	MONDO:0005556	EFO:0005761
polymyalgia rheumatica	3	MONDO:0019735	EFO:0008518
central nervous system neoplasm	3	MONDO:0006130	EFO:1000158
severe acute respiratory syndrome	3	MONDO:0005091	MONDO:0100096
plasma cell myeloma	2	MONDO:0009693	EFO:0001378
bullous pemphigoid	2	MONDO:0019082	EFO:0007187
immunoglobulin A vasculitis	2	MONDO:0019167	EFO:1000965
uveitis	2	MONDO:0020283	EFO:1001231
smoldering plasma cell myeloma	2	MONDO:0005235	EFO:0003073
Sjogren syndrome	2	MONDO:0010030	EFO:0000699
lymphoproliferative syndrome	2	MONDO:0016537	MONDO:0016537
systemic lupus erythematosus	2	MONDO:0007915	MONDO:0007915
melanoma	1	MONDO:0005105	EFO:0000756
HIV infectious disease	1	MONDO:0005109	EFO:0000764
breast neoplasm	1	MONDO:0021100	MONDO:0007254
neoplasm	1	MONDO:0005070	EFO:0000616
breast disorder	1	MONDO:0002657	EFO:0009483
hemosiderosis	1	MONDO:0001436	MONDO:0001436

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

Clinical trials

Total trials: 79.

Phase distribution

Phase	Trials
PHASE4	16
PHASE3	16
PHASE2	16
Not specified	14
PHASE1	10
PHASE1/PHASE2	5
PHASE2/PHASE3	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05626348	PHASE4	RECRUITING	The Clinical Efficacy of Immunomodulators in RA Patients
NCT00280644	PHASE4	COMPLETED	Leflunomide in Rheumatoid Arthritis
NCT00451971	PHASE4	COMPLETED	Objective Study in Rheumatoid Arthritis
NCT00563849	PHASE4	COMPLETED	Leflunomide + Methotrexate in Rheumatoid Arthritis
NCT01172639	PHASE4	COMPLETED	Effectiveness in Daily Practice of Different Treatment Strategies for Early Rheumatoid Arthritis.
NCT01659242	PHASE4	TERMINATED	Leflunomide Versus Sulfasalazine/Methotrexate in Rheumatoid Arthritis:an Ultrasound/Magnetic Resonance Imaging Study
NCT02024334	PHASE4	UNKNOWN	Efficacy Study of Leflunomide to Treat Juvenile Idiopathic Arthritis
NCT02275299	PHASE4	UNKNOWN	Study of Iguratimod Plus Methotrexate Compared to Leflunomid Plus Methotrexate in Patients With Rheumatoid Arthritis
NCT02451748	PHASE4	COMPLETED	IL-7 and IL-7R Expression in RA Patients With Active vs. Inactive Disease Treated With DMARD or CIMZIA
NCT02644499	PHASE4	COMPLETED	Comparison of Combination Disease Modifying Antirheumatic Drugs With Methotrexate Therapy in Early Rheumatoid Arthritis
NCT02703194	PHASE4	COMPLETED	Leflunomide for Maintenance of Remission in IgG4 Related Disease
NCT03449758	PHASE4	COMPLETED	Effect of Sarilumab on Patient-reported Outcomes in Patients With Active Rheumatoid Arthritis
NCT03649061	PHASE4	COMPLETED	COBRA-Slim With or Without Fast Access to TNF Blockade for Remission Induction in Early RA
NCT03739853	PHASE4	COMPLETED	Severe Psoriatic Arthritis - Early intervEntion to Control Disease: the SPEED Trial
NCT03797872	PHASE4	COMPLETED	Psoriatic Oligoarthritis Intervention With Symptomatic thErapy
NCT04020328	PHASE4	UNKNOWN	Leflunomide Plus Low Dose Corticosteroid in Immunoglobulin A (IgA) Nephropathy With Renal Insufficiency
NCT03414502	PHASE3	RECRUITING	Treatment of Rheumatoid Arthritis With DMARDs: Predictors of Response
NCT00003293	PHASE3	COMPLETED	SU-101 Compared With Procarbazine in Treating Patients With Glioblastoma Multiforme
NCT00004071	PHASE2/PHASE3	COMPLETED	Mitoxantrone and Prednisone With or Without Leflunomide in Treating Patients With Stage IV Prostate Cancer
NCT00476996	PHASE3	TERMINATED	A Study of Ocrelizumab Compared to Placebo in Patients With Active Rheumatoid Arthritis Who Don’t Have a Response to Anti-TNF-α Therapy (SCRIPT)
NCT00579878	PHASE3	COMPLETED	Triple III Comparison of Leflunomide Alone Versus Two DMARD Combinations in the Treatment of Rheumatoid Arthritis
NCT00596206	PHASE3	COMPLETED	Leflunomide EfficAcy Response Related to Dosing Regimen in Early Rheumatoid Arthritis
NCT01342016	PHASE3	TERMINATED	A Study to Compare the Efficacy and Safety of Tacrolimus Capsules With Leflunomide Tablets in Lupus Nephritis Patients
NCT01709578	PHASE3	COMPLETED	To Evaluate The Effect Of SAR153191 (REGN88) Added To Other RA Drugs In Patients With RA Who Are Not Responding To Or Intolerant Of Anti-TNF Therapy (SARIL-RA-TARGET)
NCT01727193	PHASE3	COMPLETED	The Efficacy and Safety of Leflunomide or Azathioprine Therapy in Myasthenia Gravis Patients After Expand Thymectomy
NCT01768572	PHASE3	COMPLETED	To Evaluate The Safety of SAR153191 (REGN88) and Tocilizumab Added to Other RA Drugs in Patients With RA Who Are Not Responding to or Intolerant of Anti-TNF Therapy (SARIL-RA-ASCERTAIN)
NCT01941095	PHASE3	COMPLETED	A Study of Subcutaneous Tocilizumab as Monotherapy and/or in Combination With Non-Biologic Disease Modifying Anti-Rheumatic Drugs (DMARDs) in Participants With Rheumatoid Arthritis
NCT02057250	PHASE3	COMPLETED	To Evaluate Sarilumab - SAR153191 (REGN88) - Auto-injector Device In Patients With Rheumatoid Arthritis
NCT02373202	PHASE3	COMPLETED	A Study Assessing the Safety and Efficacy of Sarilumab Added to Non-MTX DMARDs or as Monotherapy in Japanese Patients With Active Rheumatoid Arthritis (SARIL-RA-HARUKA)
NCT02930343	PHASE3	TERMINATED	Comparison of Disease Modifying Antirheumatic Drugs Therapy in Patients With RA Failing Methotrexate Monotherapy
NCT03576794	PHASE3	UNKNOWN	Treatment With Leflunomide in Patients With Polymyalgia Rheumatica
NCT04610476	PHASE3	UNKNOWN	Impact of Tapering Immunosuppressants on Maintaining Minimal Disease Activity in Adult Subjects With Psoriatic Arthritis
NCT05007678	PHASE3	COMPLETED	Targeting de Novo Pyrimidine Biosynthesis by Leflunomide for the Treatment of COVID-19 Virus Disease
NCT04508790	PHASE2	RECRUITING	Leflunomide, Pomalidomide, and Dexamethasone for the Treatment of Relapsed or Refractory Multiple Myeloma
NCT05014646	PHASE2	ACTIVE_NOT_RECRUITING	Leflunomide for the Treatment of High-Risk Smoldering Multiple Myeloma in African-American and European-American Patients
NCT05113004	PHASE2	RECRUITING	New Clinical End-points in Patients With Primary Sjögren’s Syndrome
NCT05937191	PHASE1/PHASE2	RECRUITING	Leflunomide for Idiopathic Pulmonary Hemosiderosis in Children
NCT06229340	PHASE2	RECRUITING	Leflunomide or Combination of MEK Inhibitor and Hydroxychloroquine for Refractory Patients With RAS Mutations
NCT06540937	PHASE2	RECRUITING	Phase II Clinical Study of Leflunomide in the Treatment of MEN-1 Neuroendocrine Tumor
NCT06923488	PHASE1/PHASE2	RECRUITING	Leflunomide in Combination With Decitabine for Treatment of Relapsed or Refractory Myelodysplastic Syndromes

Clinical evidence (CIViC)

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

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline, but PharmGKB curates 4 clinical and 21 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.

10 molecules share ≥1 primary target. Top 10 by shared-target count:

Molecule	Source	Status	Shared targets
ATOVAQUONE	ChEMBL	Phase 4 (approved)	DHODH
TERIFLUNOMIDE	ChEMBL	Phase 4 (approved)	DHODH
VIDOFLUDIMUS	ChEMBL	Phase 3	DHODH
ASLAN-003	ChEMBL	Phase 2	DHODH
BREQUINAR	ChEMBL	Phase 2	DHODH
CLONIXIN	ChEMBL	Phase 2	DHODH
FLUNIXIN	ChEMBL	Phase 2	DHODH
NIFLUMIC ACID	ChEMBL	Phase 2	DHODH
OXYCINCHOPHEN	ChEMBL	Phase 2	DHODH
PIPERINE	ChEMBL	Phase 2	DHODH