Levothyroxine

Summary

Levothyroxine (CHEMBL1624) is an approved small-molecule thyroid hormone targeting THRA and THRB; indicated across 8 conditions including hypothyroidism and congenital hypothyroidism.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• Targets: 2 (THRA, THRB)
• Indications: 8 conditions
• Clinical trials: 123
• Chemistry: 776.87 Da · C15H11I4NO4

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL1624
Name	Levothyroxine
Type	Small molecule
Max phase	4
FDA approved	no
PubChem CID	5819
ChEBI	CHEBI:18332
Molecular formula	C15H11I4NO4
Molecular weight	776.87
InChIKey	XUIIKFGFIJCVMT-LBPRGKRZSA-N

SMILES: C1=C(C=C(C(=C1I)OC2=CC(=C(C(=C2)I)O)I)I)C[C@@H](C(=O)O)N

IUPAC name: (2S)-2-amino-3-[4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl]propanoic acid

ChEBI definition: The L-enantiomer of thyroxine.

Pharmacological roles (ChEBI): thyroid hormone, antithyroid drug.

Other ChEBI roles (chemical / environmental): human metabolite, mouse metabolite.

Also known as: L-thyroxine, Levothyroxin, Levothyroxine, NSC-36397, Synthetic levothyroxine, Thyroxine, l-, levothyroxine, thyroxine, SID26757755, SID8139892, L-Thyroxine

Parent form; salt/anhydrous children: CHEMBL2103741, CHEMBL3989492, CHEMBL3989736

Patent coverage: 25,390 distinct patent families (81,643 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
THRA	Thyroid hormone receptor-α	Agonist		1.7%	P10827
THRB	Thyroid hormone receptor-β	Agonist	8.52	0%	P10828

Broader ChEMBL bioactivity targets: 17 (assay-derived). Sample: UDP-glucuronosyltransferase 1A1, Prelamin-A/C, Thyroid hormone receptor alpha, Thyroid hormone receptor beta, Bile acid receptor, Retinoic acid receptor RXR-alpha, Solute carrier organic anion transporter family member 4C1, Progesterone receptor, Menin/Histone-lysine N-methyltransferase MLL, Prostaglandin G/H synthase 2.

Bioactivity

ChEMBL activities: 16 potent at pChembl ≥ 5 of 29 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
THRA	7.72	EC50	19	nM	CHEMBL_ACT_20712839
THRB	6.62	EC50	240	nM	CHEMBL_ACT_20712847
PPARG	6.4	Kd	400	nM	CHEMBL_ACT_20712816
LMNA	6.15	Potency	707.9	nM	CHEMBL_ACT_3627573
RXRA	6.03	Kd	930	nM	CHEMBL_ACT_20712829
PDE4D	5.75	AC50	1800	nM	CHEMBL_ACT_25185359
TTR	5.66	IC50	2200	nM	CHEMBL_ACT_16761947
TTR	5.66	IC50	2188	nM	CHEMBL_ACT_16761969
TTR	5.66	IC50	2200	nM	CHEMBL_ACT_27718139
TTR	5.48	Ki	3300	nM	CHEMBL_ACT_29145613
UGT1A1	5.31	IC50	4900	nM	CHEMBL_ACT_15455752
UGT1A1	5.25	IC50	5600	nM	CHEMBL_ACT_15454220
NR1H4	5.11	IC50	7860	nM	CHEMBL_ACT_13348770
SLCO4C1	5.1	IC50	8000	nM	CHEMBL_ACT_11001897
PGR	5.06	AC50	8700	nM	CHEMBL_ACT_25222163
NR1I2	5.02	AC50	9500	nM	CHEMBL_ACT_25188199

Target pathways

Aggregated over 2 target gene(s): THRA, THRB.

Top Reactome pathways

9 total, by targets touching each:

Pathway	Targets	Genes
Generic Transcription Pathway	2	THRA, THRB
Nuclear Receptor transcription pathway	2	THRA, THRB
SUMOylation of intracellular receptors	2	THRA, THRB
RNA Polymerase II Transcription	2	THRA, THRB
Gene expression (Transcription)	2	THRA, THRB
SUMOylation	1	THRB
SUMO E3 ligases SUMOylate target proteins	1	THRB
Metabolism of proteins	1	THRB
Post-translational protein modification	1	THRB

Dominant GO biological processes

GO term	Targets
negative regulation of transcription by RNA polymerase II	2
thyroid hormone receptor signaling pathway	2
positive regulation of thyroid hormone receptor signaling pathway	2
regulation of transcription by RNA polymerase II	2
regulation of heart contraction	2
female courtship behavior	2
cell differentiation	2
mRNA transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	2
positive regulation of transcription by RNA polymerase II	2
retinoic acid receptor signaling pathway	2
type I pneumocyte differentiation	2
regulation of DNA-templated transcription	2
animal organ morphogenesis	2
intracellular receptor signaling pathway	2

Indications & clinical

Indications

8 indications (0 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
hypothyroidism	3	MONDO:0005420	EFO:0004705
congenital hypothyroidism	3	MONDO:0018612	MONDO:0018612
Graves disease	2	MONDO:0005364	EFO:0004237
bipolar disorder	2	MONDO:0004985	MONDO:0004985
diabetes mellitus	1	MONDO:0005015	EFO:0000400

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

Clinical trials

Total trials: 123.

Phase distribution

Phase	Trials
Not specified	43
PHASE4	29
PHASE3	15
PHASE1	14
PHASE2	12
PHASE2/PHASE3	7
PHASE1/PHASE2	2
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06653907	PHASE4	NOT_YET_RECRUITING	Levothyroxine Intervention in Pregnant Women with TSH （2.5 MIU/L-upper Limit of Reference Range） and Negative Thyroid Peroxidase Antibody
NCT00111735	PHASE4	UNKNOWN	Thyroxine Titration Study
NCT00565864	PHASE4	COMPLETED	Neurocognitive and Metabolic Effects of Mild Hypothyroidism
NCT01276782	PHASE4	WITHDRAWN	Levothyroxine in Pregnant SLE Patients
NCT01536678	PHASE4	COMPLETED	Bioequivalence of Two Levothyroxine Tablet Formulations in Healthy Indian Volunteers
NCT01631305	PHASE4	COMPLETED	Levothyroxine for Children With Euthyroid Sick Syndrome
NCT01647750	PHASE4	COMPLETED	Study of Optimal Replacement of Thyroxine in the Elderly
NCT01660126	PHASE4	COMPLETED	Thyroid Hormone Replacement for Subclinical Hypothyroidism
NCT01831869	PHASE4	UNKNOWN	Effect of L-Thyroxine on Lipid Profiles and Atherosclerosis in Subclinical Hypothyroidism
NCT01848171	PHASE4	UNKNOWN	Effects of L-thyroxine Replacement on Serum Lipid and Atherosclerosis in Hypothyroidism
NCT01853579	PHASE4	COMPLETED	The TRUST Study - Depression Substudy
NCT02186405	PHASE4	WITHDRAWN	Effects of Levothyroxine Treatment on Hemodynamic and Renal Functions in Subclinical Hypothyroidism
NCT02211053	PHASE4	TERMINATED	Evaluation of the Efficacy and Safety of Levothyroxine in Brain Death Organ Donors: a Randomized Controled Trial
NCT02316743	PHASE4	UNKNOWN	Effects of Levothyroxine Supplementation in Patients With Systolic Heart Failure and Subclinical Hypothyroidism
NCT02329379	PHASE4	WITHDRAWN	The Role of Levothyroxine on Goiter With Atypia of Undetermined Significance
NCT02491008	PHASE4	COMPLETED	Novel Biomarkers and Skeletal Outcomes Associated With Subclinical Thyroid Dysfunction
NCT02500342	PHASE4	COMPLETED	Effect of Thyroid Hormone Replacement on Fatigability in Untreated Older Adults With Subclinical Hypothyroidism
NCT02512978	PHASE4	UNKNOWN	Thyroid Hormone Replacement for Hypothyroidism and Acute Myocardial Infarction(ThyroHeart-AMI)
NCT02577367	PHASE4	WITHDRAWN	Mean Percentage of Levothyroxine Dosage Increase in Patients With Hypothyroidism Started on Enteral Feeding
NCT02832934	PHASE4	COMPLETED	The TRUST Study - CardioVascular Imaging IMT
NCT02832960	PHASE4	COMPLETED	The TRUST Trial - CardioVascular Imaging ECHO
NCT02946918	PHASE4	TERMINATED	Levothyroxine Replacement With Liquid Gel Capsules vs Tablets Post-thyroidectomy
NCT03094416	PHASE4	COMPLETED	Levothyroxine Sodium in Thyroidectomized Patients Taking Proton Pump Inhibitors
NCT03096613	PHASE4	UNKNOWN	Thyroid Hormone Replacement for Subclinical Hypothyroidism and Chronic Heart Failure (ThyroHeart-CHF)
NCT04288115	PHASE4	COMPLETED	Discontinuation of Levothyroxine Therapy for Patients With Subclinical Hypothyroidism
NCT04354896	PHASE4	COMPLETED	The Effect of Thyroid Hormone Therapy on Muscle Mass and Function in Older Adults With Subclinical Hypothyroidism
NCT04878614	PHASE4	TERMINATED	Comparison of Levothyroxine Formulation in Hypothyroid Patients With Enteral Feeding
NCT05247476	PHASE4	UNKNOWN	Type 2 Deiodinase Gene Polymorphism and the Treatment of Hypothyroidism Caused by Thyroidectomy in Thyroid Cancer Patients.
NCT05371262	PHASE4	COMPLETED	Influence of Initial Levothyroxine Dose on Neurodevelopmental and Growth Outcomes in Congenital Hypothyroidism
NCT05316922	PHASE3	RECRUITING	TSH Suppression During Radiotherapy on Thyroid Site to Prevent Iatrogenic Hypothyroidism in Pediatric Cancer Patients
NCT06345339	PHASE2/PHASE3	RECRUITING	A Study to Assess the Safety and Efficacy of Oral Armour Thyroid Compared to Synthetic T4 for the Treatment of Primary Hypothyroidism in Adult Participants
NCT06731764	PHASE2/PHASE3	RECRUITING	Novel Approaches to the Treatment of Hypothyroidism
NCT06999278	PHASE3	NOT_YET_RECRUITING	LIGHT Trial: Levothyroxine for Gestational Hypothyroidism in Recurrent Pregnancy Loss
NCT07239674	PHASE3	NOT_YET_RECRUITING	Desiccated Thyroid Extract Combined With Levothyroxine for TSH Suppression Therapy in DTC
NCT07332273	PHASE3	RECRUITING	Levothyroxine as Adjuvant to a Hypocaloric Diet for the Treatment of Obesity.
NCT00388297	PHASE3	COMPLETED	Thyroid Therapy for Mild Thyroid Deficiency in Pregnancy
NCT01306227	PHASE3	COMPLETED	L-Thyroxine Supplementation for Preterm Newborns Less Than 32 Weeks of Gestation With Hypothyroxinemia
NCT01436994	PHASE3	COMPLETED	Antithyroid Drug Treatment of Thyrotoxicosis in Young People
NCT01486667	PHASE3	UNKNOWN	Thyroxin Treatment in Sub Clinical Hypothyroidism, on the Apnea Hypopnea Index Score, Lipids and Highly Sensitive CRP
NCT01528839	PHASE2/PHASE3	COMPLETED	Supraphysiological Doses of Levothyroxine as Adjunctive Therapy in Bipolar Depression

Clinical evidence (CIViC)

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

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline, but PharmGKB curates 0 clinical and 8 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.

112 molecules share ≥1 primary target. Top 60 by shared-target count:

Molecule	Source	Status	Shared targets
AMIODARONE	ChEMBL + PubChem	Phase 4 (approved)	THRA, THRB
LIOTHYRONINE	ChEMBL + PubChem	Phase 4 (approved)	THRA, THRB
RESMETIROM	ChEMBL + PubChem	Phase 4 (approved)	THRA, THRB
ROXADUSTAT	ChEMBL	Phase 4 (approved)	THRA, THRB
EPROTIROME	ChEMBL	Phase 3	THRA, THRB
TIRATRICOL	ChEMBL	Phase 3	THRA, THRB
AXITIROME	ChEMBL	Phase 2	THRA, THRB
DETROTHYRONINE	ChEMBL	Phase 2	THRA, THRB
MB07811	ChEMBL	Phase 2	THRA, THRB
SOBETIROME	ChEMBL	Phase 2	THRA, THRB
THYROPROPIC ACID	ChEMBL	Phase 2	THRA, THRB
ACETAZOLAMIDE	ChEMBL	Phase 4 (approved)	THRB
ACETOHEXAMIDE	ChEMBL	Phase 4 (approved)	THRB
ACETYLCYSTEINE	ChEMBL	Phase 4 (approved)	THRB
ALTRETAMINE	ChEMBL	Phase 4 (approved)	THRB
AMANTADINE	ChEMBL	Phase 4 (approved)	THRB
AMILORIDE	ChEMBL	Phase 4 (approved)	THRB
AMINOCAPROIC ACID	ChEMBL	Phase 4 (approved)	THRB
AMINOPYRINE	ChEMBL	Phase 4 (approved)	THRB
AMOXAPINE	ChEMBL	Phase 4 (approved)	THRB
ATORVASTATIN	ChEMBL	Phase 4 (approved)	THRB
AZARIBINE	ChEMBL	Phase 4 (approved)	THRB
BENZBROMARONE	ChEMBL	Phase 4 (approved)	THRB
BISOPROLOL	ChEMBL	Phase 4 (approved)	THRB
BITHIONOL	ChEMBL	Phase 4 (approved)	THRB
CARBETAPENTANE	ChEMBL	Phase 4 (approved)	THRB
CHLORMADINONE	ChEMBL	Phase 4 (approved)	THRB
CHLORMEZANONE	ChEMBL	Phase 4 (approved)	THRB
CHLORPROPAMIDE	ChEMBL	Phase 4 (approved)	THRB
CLOMIPRAMINE	ChEMBL	Phase 4 (approved)	THRB
CYCLOTHIAZIDE	ChEMBL	Phase 4 (approved)	THRB
CYTARABINE	ChEMBL	Phase 4 (approved)	THRB
DAUNORUBICIN	ChEMBL	Phase 4 (approved)	THRB
DEBRISOQUIN	ChEMBL	Phase 4 (approved)	THRB
DEXTROTHYROXINE	ChEMBL	Phase 4 (approved)	THRB
DIAZOXIDE	ChEMBL	Phase 4 (approved)	THRB
DILTIAZEM	ChEMBL	Phase 4 (approved)	THRB
DIPYRIDAMOLE	ChEMBL	Phase 4 (approved)	THRB
DISOPYRAMIDE	ChEMBL	Phase 4 (approved)	THRB
DITHIAZANINE IODIDE	ChEMBL	Phase 4 (approved)	THRB
DOXORUBICIN	ChEMBL	Phase 4 (approved)	THRB
DYCLONINE	ChEMBL	Phase 4 (approved)	THRB
GENTIAN VIOLET	ChEMBL	Phase 4 (approved)	THRB
HEXACHLOROPHENE	ChEMBL	Phase 4 (approved)	THRB
HYDROCHLOROTHIAZIDE	ChEMBL	Phase 4 (approved)	THRB
IDARUBICIN	ChEMBL	Phase 4 (approved)	THRB
INAMRINONE	ChEMBL	Phase 4 (approved)	THRB
INDIGOTINDISULFONATE	ChEMBL	Phase 4 (approved)	THRB
ISOSORBIDE	ChEMBL	Phase 4 (approved)	THRB
ISOTRETINOIN	ChEMBL	Phase 4 (approved)	THRB
LEFLUNOMIDE	ChEMBL	Phase 4 (approved)	THRB
MECLOFENAMATE	ChEMBL	Phase 4 (approved)	THRB
MESALAMINE	ChEMBL	Phase 4 (approved)	THRB
METHACYCLINE	ChEMBL	Phase 4 (approved)	THRB
METHYLENE BLUE	ChEMBL	Phase 4 (approved)	THRB
METHYLENE BLUE CATION	ChEMBL	Phase 4 (approved)	THRB
METHYSERGIDE	ChEMBL	Phase 4 (approved)	THRB
METRONIDAZOLE	ChEMBL	Phase 4 (approved)	THRB
MOLSIDOMINE	ChEMBL	Phase 4 (approved)	THRB
OXYTETRACYCLINE	ChEMBL	Phase 4 (approved)	THRB