L-Citrulline

Summary

L-Citrulline (CHEMBL444814) is a phase-3 clinical-stage small-molecule EC 1.14.13.39 (nitric oxide synthase) inhibitor targeting GPRC6A; indicated across 16 conditions including acute lung injury and postpoliomyelitis syndrome.

At a glance

• Status: Max clinical phase 3 (not approved)
• Modality: Small molecule
• Targets: 1 (GPRC6A)
• Indications: 16 conditions
• Clinical trials: 73
• Chemistry: 175.19 Da · C6H13N3O3

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL444814
Name	L-Citrulline
Type	Small molecule
Max phase	3
FDA approved	no
PubChem CID	9750
ChEBI	CHEBI:16349
Molecular formula	C6H13N3O3
Molecular weight	175.19
InChIKey	RHGKLRLOHDJJDR-BYPYZUCNSA-N

SMILES: C(C[C@@H](C(=O)O)N)CNC(=O)N

IUPAC name: (2S)-2-amino-5-(carbamoylamino)pentanoic acid

ChEBI definition: The L-enantiomer of citrulline.

Pharmacological roles (ChEBI): EC 1.14.13.39 (nitric oxide synthase) inhibitor, protective agent, nutraceutical, micronutrient.

Other ChEBI roles (chemical / environmental): human metabolite, Escherichia coli metabolite, Saccharomyces cerevisiae metabolite, mouse metabolite.

Also known as: Citrulline, L-citrulline, NSC-27425, L-Citrulline, CITRULLINE, L-CITRULLINE, citrulline

Parent form; salt/anhydrous children: CHEMBL4297667

Patent coverage: 22,711 distinct patent families (73,666 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
GPRC6A	GPRC6	Full agonist	3.6	0%	Q5T6X5

Bioactivity

No ChEMBL bioactivity rows at pChembl ≥ 5 (expected for biologics / antibodies).

Target pathways

Aggregated over 1 target gene(s): GPRC6A.

Top Reactome pathways

2 total, by targets touching each:

Pathway	Targets	Genes
G alpha (q) signalling events	1	GPRC6A
Class C/3 (Metabotropic glutamate/pheromone receptors)	1	GPRC6A

Dominant GO biological processes

GO term	Targets
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1
calcium-mediated signaling	1
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1
response to amino acid	1
regulation of testosterone biosynthetic process	1
signal transduction	1
G protein-coupled receptor signaling pathway	1

Indications & clinical

Indications

16 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
acute lung injury	3	MONDO:0015796	EFO:0004610
postpoliomyelitis syndrome	3	MONDO:0017416	EFO:0007454
intermittent vascular claudication	2	MONDO:0005295	EFO:0003876
peripheral arterial disease	2	MONDO:0005386	EFO:0004265
respiratory failure	2	MONDO:0021113	EFO:0009686
asthma	2	MONDO:0004979	MONDO:0004979
neoplasm	2	MONDO:0005070	MONDO:0004992
hypertensive disorder	1	MONDO:0005044	EFO:0000537
MELAS syndrome	1	MONDO:0010789	Orphanet:550
ventricular septal defect	1	MONDO:0002070	MONDO:0002070
type 2 diabetes mellitus	1	MONDO:0005148	MONDO:0005148
sickle cell disease	1	MONDO:0011382	MONDO:0011382
bronchopulmonary dysplasia	1	MONDO:0019091	MONDO:0019091
atrial septal defect	1	MONDO:0006664	MONDO:0007172

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

Clinical trials

Total trials: 73.

Phase distribution

Phase	Trials
Not specified	39
PHASE1	13
PHASE3	7
PHASE2	6
PHASE1/PHASE2	5
EARLY_PHASE1	2
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06212765	PHASE3	NOT_YET_RECRUITING	Oral Citrulline Supplementation in COPD Patients With Malnutrition
NCT06989567	PHASE3	NOT_YET_RECRUITING	A Study of Intravenous L-Citrulline in Patients Aged 6-21 Years Old With Sickle Cell Disease Presenting to Emergency Departments in Acute Vaso-Occlusive Crisis
NCT00335244	PHASE3	COMPLETED	Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery
NCT00628381	PHASE3	UNKNOWN	L-citrulline Supplementation During Sepsis
NCT01386034	PHASE3	COMPLETED	Effects of Oral Citrulline on Protein Metabolism in Patients With Intestinal Failure (Citrugrêle 2)
NCT02801695	PHASE2/PHASE3	COMPLETED	Evaluation of the Efficacy of Citrulline Supplementation on the Delay of Delivery for Women Hospitalized for Pre-eclampsia (CITRUPE)
NCT02891837	PHASE3	COMPLETED	L-citrulline for Prevention of Sequelae of Acute Lung Injury in Pediatrics Undergoing Cardiopulmonary Bypass for Heart Defects
NCT05253209	PHASE3	TERMINATED	A Study Evaluating the Efficacy and Safety of IV L-Citrulline for the Prevention of Clinical Sequelae of Acute Lung Injury Induced by Cardiopulmonary Bypass in Pediatric Patients Undergoing Surgery for Congenital Heart Defects
NCT05259904	PHASE2	RECRUITING	Study to Improve Deployment Related Asthma by Using L-Citrulline Supplementation
NCT06635902	PHASE2	RECRUITING	Intravenous L-Citrulline for Vaso-occlusive Pain Episode in Sickle Cell Disease
NCT00201214	PHASE1/PHASE2	COMPLETED	Citrulline for Children Undergoing Cardiopulmonary Bypass Surgery
NCT00223730	PHASE2	COMPLETED	Chemotherapy Toxicity Reduction Via Urea Cycle Support
NCT00351286	PHASE2	UNKNOWN	Efficacy Study of Oral L-Citrulline in Patients Taking Simvastatin With Peripheral Arterial Disease
NCT01120964	PHASE1/PHASE2	COMPLETED	Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery : Revised Protocol
NCT01462591	PHASE1/PHASE2	COMPLETED	L-citrulline Supplementation & Cold Exposure
NCT02018731	PHASE2	COMPLETED	L-citrulline and Metformin in Becker’s Muscular Dystrophy
NCT02104375	PHASE1/PHASE2	COMPLETED	L-citrulline Supplementation, Cold Exposure, & Post-Exercise Muscle Ischemia
NCT04570384	PHASE2	COMPLETED	Intravenous L-Citrulline Influence on the Need for Invasive Mechanical Ventilation for Acute Hypoxemic Respiratory Failure in Patients With COVID-19
NCT04852172	PHASE1/PHASE2	TERMINATED	L-citrulline Injection in Patients Aged 6-21 Years Old with Sickle Cell Disease Presenting with Vaso-Occlusive Crisis (VOC)
NCT06312748	PHASE1	RECRUITING	Novel Approaches for Improving Vascular Function in Veterans With HFpEF
NCT00343954	PHASE1	UNKNOWN	PK and PD Responses to Oral L-Citrulline in Patients With Sickle Cell Disease
NCT00742534	PHASE1	WITHDRAWN	Phase 1 Intravenous Citrulline for the Prevention of Bronchopulmonary Dysplasia in Preterm Infants
NCT00743210	PHASE1	COMPLETED	Oral L-Citrulline and ADMA in Pregnancy
NCT00756080	PHASE1	COMPLETED	Effects of Oral Citrulline on Protein Metabolism in Healthy Humans: a Prospective, Randomized, Double-blind , Cross-over Study (Citrugrêle)
NCT01715844	PHASE1	COMPLETED	L-Citrulline Supplementation Pilot Study for Overweight Late Onset Asthmatics
NCT02314689	PHASE1	COMPLETED	A Dose Escalation Study of Intravenous L-citrulline in Steady-state Sickle Cell Disease
NCT02659644	PHASE1	WITHDRAWN	A Study of Oral L-citrulline in Sickle Cell Disease
NCT02697240	PHASE1	COMPLETED	A Phase 1 Study of Continuous Intravenous L-citrulline During Sickle Cell Pain Crisis or Acute Chest Syndrome
NCT03649932	PHASE1	COMPLETED	Enteral L Citrulline Supplementation in Preterm Infants - Safety, Efficacy and Dosing
NCT03952234	PHASE1	COMPLETED	L-Citrulline Dose Finding Safety Study in MELAS
NCT04979793	PHASE1	SUSPENDED	Role of L-citrulline in Prevention of Pregnancy Associated Hypertension
NCT05722860	PHASE1	COMPLETED	L-Citrulline and Endothelial Function
NCT03542812	EARLY_PHASE1	TERMINATED	L-citrulline and Pulmonary Hypertension Associated With Bronchopulmonary Dysplasia
NCT04770155	EARLY_PHASE1	TERMINATED	Vascular Dysfunction in Black Individuals: Roles of Nitric Oxide and Endothelin-1
NCT05636397	Not specified	RECRUITING	Safety and PK-PD Study of Oral L-CIT in Preterm Infants With BPD±PH and NEC
NCT05934318	Not specified	RECRUITING	L-ArGinine to pRevent advErse prEgnancy Outcomes (AGREE)
NCT06426147	Not specified	RECRUITING	L-citrulline to Improve Adverse Outcomes in Admitted Children (EChiLiBRiST, Clinical Trial 2, Inpatients)
NCT00714675	Not specified	COMPLETED	Citrulline and Protein Metabolism in the Malnourished Elderly People
NCT00950976	Not specified	COMPLETED	Dose-response Enteral Citrulline for Normal Healthy Volunteers and Surgery Patients
NCT01062828	Not specified	TERMINATED	Defining Normal Citrulline Levels as a Diagnostic Tool for Screening of Gastrointestinal Disease in Premature Infants

Clinical evidence (CIViC)

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

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline or drug-level clinical/variant annotations in PharmGKB for this molecule.

Related molecules

Related molecules

No competitor molecules sharing a primary target (ChEMBL phase ≥2 or PubChem drug-class).