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Details

Stereochemistry ABSOLUTE
Molecular Formula C7H16N4O2
Molecular Weight 188.2275
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of TILARGININE

SMILES

CNC(=N)NCCC[C@H](N)C(O)=O

InChI

InChIKey=NTNWOCRCBQPEKQ-YFKPBYRVSA-N
InChI=1S/C7H16N4O2/c1-10-7(9)11-4-2-3-5(8)6(12)13/h5H,2-4,8H2,1H3,(H,12,13)(H3,9,10,11)/t5-/m0/s1

HIDE SMILES / InChI

Molecular Formula C7H16N4O2
Molecular Weight 188.2275
Charge 0
Count
MOL RATIO 1 MOL RATIO (average)
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Description

Tilarginine is L-N-monomethyl arginine (L -NMMA), a non-selective inhibitor of nitric oxide synthase (NOS), which has been studied in the treatment of septic shock and cardiogenic shock complicating myocardial infarction. Despite strong evidence that excessive nitric oxide (NO) production plays a pivotal role in the pathogenesis of septic shock and may contribute to the pathogenesis of cardiogenic shock complicating myocardial infarction, outcome studies in these two disorders have proved disappointing. Tilarginine therapy was associated with an excess mortality, particularly at doses > 5 mg/(kg h), in septic shock, whereas the effects of a lower dose (1 mg/(kg h)) in cardiogenic shock complicating myocardial infarction were neutral. The excess mortality in patients with septic shock was almost certainly the result of unfavorable hemodynamic changes induced by Tilarginine (decreased cardiac output, increased pulmonary vascular resistance and reduced tissue oxygen delivery) whereas the lack of benefit in patients with cardiogenic shock complicating myocardial infarction may have been because the dose of Tilarginine was too low.

Originator

Approval Year

Targets

Primary TargetPharmacologyConditionPotency
90.0 nM [IC50]
1000.0 nM [IC50]
540.0 nM [IC50]

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown
Primary
Unknown
Primary
Unknown

Cmax

ValueDoseCo-administeredAnalytePopulation
12.9 μg/mL
3 mg/kg single, intravenous
TILARGININE plasma
Homo sapiens
2.03 μg/mL
1 mg/kg/h single, intravenous
TILARGININE plasma
Homo sapiens
5.53 μg/mL
2.5 mg/kg/h single, intravenous
TILARGININE plasma
Homo sapiens
22.9 μg/mL
5 mg/kg/h single, intravenous
TILARGININE plasma
Homo sapiens
51.9 μg/mL
10 mg/kg/h single, intravenous
TILARGININE plasma
Homo sapiens
128 μg/mL
20 mg/kg/h single, intravenous
TILARGININE plasma
Homo sapiens

AUC

ValueDoseCo-administeredAnalytePopulation
260.4 μg × min/mL
3 mg/kg single, intravenous
TILARGININE plasma
Homo sapiens
16.6 μg × h/mL
1 mg/kg/h single, intravenous
TILARGININE plasma
Homo sapiens
40.8 μg × h/mL
2.5 mg/kg/h single, intravenous
TILARGININE plasma
Homo sapiens
175 μg × h/mL
5 mg/kg/h single, intravenous
TILARGININE plasma
Homo sapiens
443 μg × h/mL
10 mg/kg/h single, intravenous
TILARGININE plasma
Homo sapiens
1640 μg × h/mL
20 mg/kg/h single, intravenous
TILARGININE plasma
Homo sapiens

T1/2

ValueDoseCo-administeredAnalytePopulation
63.5 min
3 mg/kg single, intravenous
TILARGININE plasma
Homo sapiens
2.3 h
1 mg/kg/h single, intravenous
TILARGININE plasma
Homo sapiens
2.1 h
2.5 mg/kg/h single, intravenous
TILARGININE plasma
Homo sapiens
3.1 h
5 mg/kg/h single, intravenous
TILARGININE plasma
Homo sapiens
2.4 h
10 mg/kg/h single, intravenous
TILARGININE plasma
Homo sapiens
7.6 h
20 mg/kg/h single, intravenous
TILARGININE plasma
Homo sapiens

Overview

CYP3A4CYP2C9CYP2D6hERG



OverviewOther

Other InhibitorOther SubstrateOther Inducer


Drug as perpetrator​

PubMed

Sample Use Guides

In Vivo Use Guide
Tilarginine was given as an intravenous infusion starting with a dose of 2.5 mg/(kg h), which could be subsequently increased in an incremental manner up to a maximum dose of 20 mg/(kg h).
Route of Administration: Intravenous
In Vitro Use Guide
L-NMMA (Tilarginine) was assayed for ability to inhibit NO production in human colorectal adenocarcinoma (DLD-1) cells preincubated with a cytokine cocktail. Cells were grown to confluence in 12-well plates. Cytokines or other agents were added to fresh media (1 mL/well). At 18-24-h postinduction, culture supernatants were harvested and stored at -20 C for nitrite analysis. Nitrite was measured spectrophotometrically using the Griess reagent
Substance Class Chemical
Record UNII
27JT06E6GR
Record Status Validated (UNII)
Record Version