Tilarginine

Summary

Tilarginine (CHEMBL256147) is a phase-3 clinical-stage small molecule targeting NOS3, NOS2, and NOS1; indicated across 11 conditions including anemia and sickle cell disease.

At a glance

• Status: Max clinical phase 3 (not approved)
• Modality: Small molecule
• Targets: 3 (NOS3, NOS2, NOS1)
• Indications: 11 conditions
• Clinical trials: 39
• Chemistry: 188.23 Da · C7H16N4O2

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL256147
Name	Tilarginine
Type	Small molecule
Max phase	3
FDA approved	no
PubChem CID	132862
ChEBI	CHEBI:28229
Molecular formula	C7H16N4O2
Molecular weight	188.23
InChIKey	NTNWOCRCBQPEKQ-YFKPBYRVSA-N

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

IUPAC name: (2S)-2-amino-5-[(N’-methylcarbamimidoyl)amino]pentanoic acid

ChEBI definition: A L-arginine derivative with a Nω-methyl substituent.

Also known as: .omega.-n-methylarginine, L-NMMA, Ng-methylarginine, Omega-n-methylarginine, Omega-n-methylated arginine, Tilarginina, Tilarginine, SID11113694, SID90340995, SID11111490, N-monomethyl arginine, L-NG-monomethyl arginine

Parent form; salt/anhydrous children: CHEMBL1256175, CHEMBL1744478, CHEMBL3217190

Patent coverage: 780 distinct patent families (2,020 SureChEMBL compound mentions), from 3 matched compound structure(s). One matched structure accounts for 1,715 (85%) 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
NOS3	Endothelial NOS	Inhibition	6.4		P29474
NOS2	Inducible NOS	Inhibition	6.07	0.1%	P35228
NOS1	Neuronal NOS	Inhibition	6.08	0.2%	P29475

Broader ChEMBL bioactivity targets: 12 (assay-derived). Sample: Menin/Histone-lysine N-methyltransferase MLL, Nitric oxide synthase 1, Nitric oxide synthase, inducible, Cytochrome P450 1A2, Nitric oxide synthase, inducible, Nitric oxide synthase 1, Cytochrome P450 2C19, Nitric oxide synthase, inducible, Nitric oxide synthase 1, Nitric oxide synthase 3.

Bioactivity

ChEMBL activities: 47 potent at pChembl ≥ 5 of 62 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
NOS2	8.74	IC50	1.8	nM	CHEMBL_ACT_10939321
NOS1	7.05	IC50	90	nM	CHEMBL_ACT_977943
P29476	7	IC50	100	nM	CHEMBL_ACT_324043
P29476	7	IC50	100	nM	CHEMBL_ACT_516296
P29476	6.7	Ki	200	nM	CHEMBL_ACT_12667535
NOS2	6.52	IC50	300	nM	CHEMBL_ACT_324042
NOS3	6.52	IC50	300	nM	CHEMBL_ACT_324044
NOS2	6.52	IC50	300	nM	CHEMBL_ACT_516295
NOS3	6.52	IC50	300	nM	CHEMBL_ACT_516297
NOS3	6.48	IC50	330	nM	CHEMBL_ACT_977942
NOS2	6.47	IC50	340	nM	CHEMBL_ACT_977941
NOS3	6.4	Ki	400	nM	CHEMBL_ACT_192945
NOS3	6.4	Ki	400	nM	CHEMBL_ACT_463985
P29476	6.3	Ki	500	nM	CHEMBL_ACT_25610675
NOS3	6.27	IC50	540	nM	CHEMBL_ACT_1199892
NOS3	6.27	IC50	540	nM	CHEMBL_ACT_857199
NOS3	6.19	IC50	650	nM	CHEMBL_ACT_10939309
NOS3	6.19	IC50	650	nM	CHEMBL_ACT_12085130
NOS1	6.08	Ki	840	nM	CHEMBL_ACT_192946
NOS1	6.08	Ki	840	nM	CHEMBL_ACT_463986
NOS2	6.07	Ki	860	nM	CHEMBL_ACT_192944
NOS2	6.07	Ki	860	nM	CHEMBL_ACT_463984
NOS1	6.05	IC50	890	nM	CHEMBL_ACT_1199891
NOS1	6.05	IC50	890	nM	CHEMBL_ACT_857198
NOS1	6.02	IC50	950	nM	CHEMBL_ACT_10939297
NOS1	6.02	IC50	950	nM	CHEMBL_ACT_12085140
NOS2	6	IC50	1000	nM	CHEMBL_ACT_1199893
NOS2	6	IC50	1000	nM	CHEMBL_ACT_857200
P29477	5.64	IC50	2300	nM	CHEMBL_ACT_15660060
NOS1	5.57	IC50	2700	nM	CHEMBL_ACT_308860

Target pathways

Aggregated over 3 target gene(s): NOS3, NOS2, NOS1.

Top Reactome pathways

13 total, by targets touching each:

Pathway	Targets	Genes
ROS and RNS production in phagocytes	3	NOS1, NOS2, NOS3
Nitric oxide stimulates guanylate cyclase	3	NOS1, NOS2, NOS3
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation	1	NOS3
eNOS activation	1	NOS3
NOSTRIN mediated eNOS trafficking	1	NOS3
NOSIP mediated eNOS trafficking	1	NOS3
VEGFR2 mediated vascular permeability	1	NOS3
Ion homeostasis	1	NOS1
Interleukin-4 and Interleukin-13 signaling	1	NOS2
Extra-nuclear estrogen signaling	1	NOS3
Peroxisomal protein import	1	NOS2
Inhibition of nitric oxide production	1	NOS2
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	NOS3

Dominant GO biological processes

GO term	Targets
L-arginine catabolic process	3
nitric oxide biosynthetic process	3
obsolete nitric oxide mediated signal transduction	3
response to hormone	3
response to lipopolysaccharide	3
cell redox homeostasis	3
negative regulation of blood pressure	3
regulation of sodium ion transport	2
potassium ion transport	2
calcium ion transport	2
response to heat	2
vasodilation	2
negative regulation of potassium ion transport	2
negative regulation of calcium ion transport	2
blood circulation	2

Indications & clinical

Indications

11 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
anemia	2	MONDO:0002280	EFO:0004272
sickle cell disease	2	MONDO:0011382	MONDO:0011382
hyperlipidemia	2	MONDO:0021187	MONDO:0021187
HIV infectious disease	1	MONDO:0005109	EFO:0000764
breast neoplasm	1	MONDO:0021100	MONDO:0007254
congestive heart failure	1	MONDO:0005009	EFO:0000373
hypertensive disorder	1	MONDO:0005044	EFO:0000537
cirrhosis of liver	1	MONDO:0005155	EFO:0001422

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

Clinical trials

Total trials: 39.

Phase distribution

Phase	Trials
PHASE1	18
Not specified	8
PHASE2	6
PHASE4	3
PHASE3	1
PHASE2/PHASE3	1
PHASE1/PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00410085	PHASE4	COMPLETED	Renal Hemodynamics and Tubular Function in Patients With Obstructive Sleep Apnea and Healthy Controls
NCT01701973	PHASE4	COMPLETED	Effect of DPP4 Inhibition on Growth Hormone Secretion
NCT01744236	PHASE4	COMPLETED	SAFEGUARD: Pleiotropic Effects of Incretin Based Therapies
NCT00112281	PHASE3	TERMINATED	A Study of the Safety and Efficacy of Nitric Oxide Reduction in Patients With Cardiogenic Shock After a Heart Attack
NCT03534661	PHASE2/PHASE3	COMPLETED	L-NMMA on GLP-2 Mediated Intestinal Lipoprotein Release
NCT05660083	PHASE2	RECRUITING	Alpelisib/iNOS Inhibitor/Nab-paclitaxel in Patients With HER2 Negative Metaplastic Breast Cancer (MpBC)
NCT00009581	PHASE2	COMPLETED	Nitric Oxide to Improve Blood Flow in Sickle Cell Disease
NCT00048477	PHASE2	COMPLETED	Effects of Nitrite on Blood Vessel Dilation in Normal Volunteers
NCT00406731	PHASE2	WITHDRAWN	Role of Endothelin- and Nitric Oxide-system in the Regulation of Optic Nerve Head Blood Flow During Changes in Ocular Perfusion Pressure
NCT00431392	PHASE2	COMPLETED	Mechanisms of Choroidal Blood Flow Changes During Dark/Light Transitions
NCT00508989	PHASE2	COMPLETED	Niacin to Improve Blood Flow in People With Sickle Cell Disease
NCT02834403	PHASE1/PHASE2	COMPLETED	L-NMMA Plus Taxane Chemotherapy in Refractory Locally Advanced or Metastatic Triple Negative Breast Cancer Patients
NCT00004575	PHASE1	COMPLETED	Effects of Miconazole on Blood Flow
NCT00005107	PHASE1	UNKNOWN	Role of Nitric Oxide in Cirrhosis: Relationship With Systemic Hemodynamics, Renal Function, Vasoactive Systems and Endotoxemia
NCT00072826	PHASE1	COMPLETED	Atorvastatin Therapy to Improve Endothelial Function in Sickle Cell Disease
NCT00076414	PHASE1	COMPLETED	The Effect of Lopinavir/Ritonavir on Endothelial Function
NCT00095472	PHASE1	COMPLETED	Therapeutic Application of Intravascular Nitrite for Sickle Cell Disease
NCT00185003	PHASE1	COMPLETED	Blockade of Vascular Potassium Channels During Human Endotoxemia
NCT00327080	PHASE1	TERMINATED	Sildenafil to Treat HIV-Associated Pulmonary Hypertension
NCT00344734	PHASE1	COMPLETED	Effects of Acute L-NMMA Treatment on Renal Hemodynamics and Vasoactive Hormones in Patients With Congestive Heart Failure
NCT00344916	PHASE1	COMPLETED	Phase 1 Study of L-NMMA in Patients With Liver Cirrhosis
NCT00345137	PHASE1	COMPLETED	Effects of Systemic NO-Inhibition on Renal Hemodynamics in Patiens With Polycystic Kidney Disease and Chronic Glomerulonephritis
NCT00345150	PHASE1	COMPLETED	Effects of Inhibition of NO-Synthesis on Renal Hemodynamics and Sodium Excretion in Patients With Essential Hypertension and Healthy Controls
NCT00580619	PHASE1	COMPLETED	Autonomic Nervous System and Chronic Fatigue Syndrome
NCT00690534	PHASE1	COMPLETED	Insulin and Sarcopenia in the Elderly
NCT01070940	PHASE1	COMPLETED	L-NMMA Dose-response Study in Healthy Subjects
NCT01122407	PHASE1	COMPLETED	Pathophysiology of Cardiometabolic Risk Factors in African Americans
NCT01860911	PHASE1	COMPLETED	Plasma Triglyceride Extraction by The Muscle
NCT03066115	PHASE1	WITHDRAWN	Impact of NOS, COX, and ROS Inhibition on Cerebral Blood Flow Regulation
NCT03236935	PHASE1	COMPLETED	Phase Ib of L-NMMA and Pembrolizumab
NCT00708357	EARLY_PHASE1	TERMINATED	Does eNOS Gene Polymorphism Play a Role in the Maintenance of Basal Vascular Tone in the Choroid or Optic Nerve Head?
NCT03625349	Not specified	ACTIVE_NOT_RECRUITING	Passive Limb Movement: A Tool to Assess Vascular Health and Guide Rehabilitation
NCT00178919	Not specified	COMPLETED	Nitric Oxide and the Autonomic Nervous System
NCT00431665	Not specified	COMPLETED	Effect of Elevated Plasma-Free-Fatty-Acids on Renal Hemodynamic Parameters
NCT00685945	Not specified	COMPLETED	Renin-Angiotensin Aldosterone System and Fibrinolysis Interaction in Humans-Specific Aim 3
NCT00806741	Not specified	COMPLETED	Role of Nitric Oxide in Optic Nerve Head Blood Flow Regulation During Isometric Exercise in Healthy Humans
NCT00914394	Not specified	TERMINATED	Role of Nitric Oxide in Optic Nerve Head Blood Flow Regulation During Experimental Increase of Intraocular Pressure in Healthy Humans
NCT01617551	Not specified	UNKNOWN	Effect of Renal Denervation on NO-mediated Sodium Excretion and Plasma Levels of Vasoactive Hormones
NCT02183779	Not specified	UNKNOWN	PORH and Response to Cold in Raynaud’s Phenomenon.

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

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.

12 molecules share ≥1 primary target. Top 12 by shared-target count:

Molecule	Source	Status	Shared targets
CHLORZOXAZONE	ChEMBL	Phase 4 (approved)	NOS1, NOS2, NOS3
GW-274150	ChEMBL	Phase 2	NOS1, NOS2, NOS3
L-NAME	ChEMBL	Phase 2	NOS1, NOS2, NOS3
PIMAGEDINE	ChEMBL	Phase 2	NOS1, NOS2, NOS3
KD7040	ChEMBL	Phase 2	NOS1, NOS2
SAPROPTERIN	ChEMBL + PubChem	Phase 4 (approved)	NOS1
ARGININE	ChEMBL	Phase 3	NOS2
CURCUMIN	ChEMBL	Phase 3	NOS2
AMINOTHIAZOLE	ChEMBL	Phase 2	NOS1
BARDOXOLONE	ChEMBL	Phase 2	NOS2
PRAXADINE	ChEMBL	Phase 2	NOS1
rifampin	PubChem	Approved	NOS2