Carglumic Acid

Identification

Name
Carglumic Acid
Accession Number
DB06775
Type
Small Molecule
Groups
Approved
Description

Carglumic acid is an orphan drug used for the treatment of hyperammonaemia in patients with N-acetylglutamate synthase deficiency. This rare genetic disorder results in elevated blood levels of ammonia, which can eventually cross the blood–brain barrier and cause neurologic problems, cerebral edema, coma, and death. Carglumic acid was approved by the U.S. Food and Drug Administration (FDA) on 18 March 2010.

Structure
Thumb
Synonyms
  • (2S)-2-(Carbamoylamino)pentanedioic acid
  • (S)-2-ureidopentanedioic acid
  • Acide carglumique
  • Acido carglumico
  • Acidum carglumicum
  • Carbamino-L-glutamic acid
  • Carbamylglutamic acid
  • L-N-Carbamoylglutamic acid
  • N-Carbamoyl-L-Glutamic Acid
  • N-Carbamyl-L-glutamate
  • N-Carbamylglutamate
  • Ureidoglutaric acid
External IDs
OE 312 / OE-312
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CarbagluTablet, for suspension200 mgOralOrphan Europe S.A.R.L.2003-01-24Not applicableEu
CarbagluTablet, orally disintegrating200 mgOralOrphan Europe Sarl2015-09-08Not applicableCanada
CarbagluTablet, for suspension200 mgOralOrphan Europe S.A.R.L.2003-01-24Not applicableEu
CarbagluTablet200 mg/1OralOrphan Europe Sarl2010-03-18Not applicableUs
CarbagluTablet, for suspension200 mgOralOrphan Europe S.A.R.L.2003-01-24Not applicableEu
International/Other Brands
Carbaglu
Categories
UNII
5L0HB4V1EW
CAS number
1188-38-1
Weight
Average: 190.154
Monoisotopic: 190.05897144
Chemical Formula
C6H10N2O5
InChI Key
LCQLHJZYVOQKHU-VKHMYHEASA-N
InChI
InChI=1S/C6H10N2O5/c7-6(13)8-3(5(11)12)1-2-4(9)10/h3H,1-2H2,(H,9,10)(H,11,12)(H3,7,8,13)/t3-/m0/s1
IUPAC Name
(2S)-2-(carbamoylamino)pentanedioic acid
SMILES
NC(=O)N[C@@H](CCC(O)=O)C(O)=O

Pharmacology

Indication

For the treatment of acute and chronic hyperammonaemia in patients with N-acetylglutamate synthase (NAGS) deficiency. This enzyme is an important component of the urea cycle to prevent build up of neurotoxic ammonium in the blood.

Associated Conditions
Pharmacodynamics

The median Tmax of Carbaglu was 3 hours (range: 2-4). The initial daily dose ranges from 100 to 250 mg/kg, adjusted thereafter to maintain normal plasma levels of ammonia.

Mechanism of action

Carglumic acid is a synthetic structural analogue of N-acetylglutamate (NAG), which is an essential allosteric activator of the liver enzyme carbamoyl phosphate synthetase 1 (CPS1). CPS1 is found in the mitochondria and is the first enzyme of the urea cycle, which converts ammonia into urea. Carglumic acid acts as a replacement for NAG in NAGS deficiency patients by activating CPS1 but it does not help to regulate the urea cycle.

TargetActionsOrganism
ACarbamoyl-phosphate synthase [ammonia], mitochondrial
allosteric modulator
Human
Absorption

30% bioavailability; Cmax, mean, 100 mg/kg dose = 2.6 μg/mL (range of 1.9 - 4.8)
Carglumic acid is not subject to to intracellular degradation.

Volume of distribution

The apparent volume of distribution was 2657 L (range: 1616-5797).

Protein binding
Not Available
Metabolism

A proportion of carglumic acid may be metabolized by the intestinal bacterial flora. The likely end product of carglumic acid metabolism is carbon dioxide, eliminated through the lungs.

Route of elimination

Following administration of a single radiolabeled oral dose of 100 mg/kg of body weight, 9% of the dose was excreted unchanged in the urine and up to 60% of the dose was excreted unchanged in the feces.

Half life

Median values for the terminal half-life was 5.6 hours (range 4.3-9.5).

Clearance

The apparent total clearance was 5.7 L/min (range 3.0-9.7), the renal clearance was 290 mL/min (range 204-445), and the 24-hour urinary excretion was 4.5 % of the dose (range 3.5-7.5).

Toxicity

LD50, oral, mouse: >1000 mg/kg

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
No interactions found.
Food Interactions
Not Available

References

General References
  1. Elpeleg O, Shaag A, Ben-Shalom E, Schmid T, Bachmann C: N-acetylglutamate synthase deficiency and the treatment of hyperammonemic encephalopathy. Ann Neurol. 2002 Dec;52(6):845-9. [PubMed:12447942]
  2. Caldovic L, Morizono H, Daikhin Y, Nissim I, McCarter RJ, Yudkoff M, Tuchman M: Restoration of ureagenesis in N-acetylglutamate synthase deficiency by N-carbamylglutamate. J Pediatr. 2004 Oct;145(4):552-4. [PubMed:15480384]
  3. Thompson CA: Carglumic acid approved to treat genetic hyperammonemia. Am J Health Syst Pharm. 2010 May 1;67(9):690. doi: 10.2146/news100031. [PubMed:20410539]
  4. Haberle J: Role of carglumic acid in the treatment of acute hyperammonemia due to N-acetylglutamate synthase deficiency. Ther Clin Risk Manag. 2011;7:327-32. doi: 10.2147/TCRM.S12703. Epub 2011 Aug 2. [PubMed:21941437]
  5. Carbaglu [Link]
External Links
Human Metabolome Database
HMDB0015673
KEGG Drug
D07130
KEGG Compound
C05829
PubChem Compound
121396
PubChem Substance
99443290
ChemSpider
108351
ChEBI
71028
ChEMBL
CHEMBL1201780
PharmGKB
PA165958402
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
ATC Codes
A16AA05 — Carglumic acid
AHFS Codes
  • 40:10.00 — Ammonia Detoxicants
FDA label
Download (351 KB)
MSDS
Download (82.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2RecruitingTreatmentCarbamoyl-Phosphate Synthase I Deficiency Disease / Late-onset CPS1 Deficiency (CPSD) / Late-onset Ornithine Transcarbamylase Deficiency (OTCD) / Methylmalonic Acidemia / Methylmalonic Acidemia (MMA) / Ornithine Carbamoyltransferase Deficiency / Propionic Acidemia (PA) / Propionic Acidemia, Type I and/or Type II1
2TerminatedTreatmentMethylmalonic Acidemia (MMA) / Propionic Acidemia (PA)1
2WithdrawnTreatmentCarbamyl Phosphate Synthetase Deficiency / Inborn Errors of Metabolism / Methylmalonic Acidemia / Propionic Acidemia (PA) / Urea Cycle Disorders, Inborn1
2, 3CompletedTreatmentInborn Errors of Metabolism1
3Active Not RecruitingTreatmentMethylmalonic Acidemia / Propionic Acidemia (PA)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral200 mg/1
Tablet, for suspensionOral200 mg
Tablet, orally disintegratingOral200 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP-1.097MSDS
Predicted Properties
PropertyValueSource
Water Solubility19.1 mg/mLALOGPS
logP-1.1ALOGPS
logP-1.4ChemAxon
logS-1ALOGPS
pKa (Strongest Acidic)3.36ChemAxon
pKa (Strongest Basic)-2.3ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area129.72 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity39.41 m3·mol-1ChemAxon
Polarizability16.78 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.8269
Blood Brain Barrier+0.9054
Caco-2 permeable-0.8554
P-glycoprotein substrateNon-substrate0.6682
P-glycoprotein inhibitor INon-inhibitor0.9775
P-glycoprotein inhibitor IINon-inhibitor0.9945
Renal organic cation transporterNon-inhibitor0.9589
CYP450 2C9 substrateNon-substrate0.748
CYP450 2D6 substrateNon-substrate0.8273
CYP450 3A4 substrateNon-substrate0.7701
CYP450 1A2 substrateNon-inhibitor0.9399
CYP450 2C9 inhibitorNon-inhibitor0.9371
CYP450 2D6 inhibitorNon-inhibitor0.955
CYP450 2C19 inhibitorNon-inhibitor0.9447
CYP450 3A4 inhibitorNon-inhibitor0.8408
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9909
Ames testNon AMES toxic0.8509
CarcinogenicityNon-carcinogens0.9372
BiodegradationReady biodegradable0.912
Rat acute toxicity1.3576 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9741
hERG inhibition (predictor II)Non-inhibitor0.9818
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - GC-EI-TOFGC-MSsplash10-0a4j-1941000000-35634903a91e28863b1f
GC-MS Spectrum - GC-EI-TOFGC-MSsplash10-0udi-0910000000-e949449c58d3f3cc2c15
GC-MS Spectrum - GC-EI-TOFGC-MSsplash10-000i-9711000000-60f15bbb265b788ea08a
GC-MS Spectrum - GC-EI-TOFGC-MSsplash10-0fk9-0900000000-5d552fa6b00d42d5e114
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-000j-0900000000-b40c000081e1b7470cc1
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-002b-0900000000-eb1fe6fcbdc6f376370e
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-0udi-0900000000-245f4056f629592bd99f
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-0udi-4900000000-3a5f21eb40fd1821e24f
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-0pb9-9500000000-67aafe80496b10392ef0

Taxonomy

Description
This compound belongs to the class of organic compounds known as glutamic acid and derivatives. These are compounds containing glutamic acid or a derivative thereof resulting from reaction of glutamic acid at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Glutamic acid and derivatives
Alternative Parents
Fatty acids and conjugates / Dicarboxylic acids and derivatives / Isoureas / Carboxylic acids / Carboximidamides / Organopnictogen compounds / Organic oxides / Imines / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Glutamic acid or derivatives / Dicarboxylic acid or derivatives / Fatty acid / Isourea / Carboximidamide / Carboxylic acid / Carboximidic acid derivative / Organic oxide / Organic nitrogen compound / Hydrocarbon derivative
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
ureas, N-acyl-L-glutamic acid (CHEBI:71028)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Allosteric modulator
General Function
Phospholipid binding
Specific Function
Involved in the urea cycle of ureotelic animals where the enzyme plays an important role in removing excess ammonia from the cell.
Gene Name
CPS1
Uniprot ID
P31327
Uniprot Name
Carbamoyl-phosphate synthase [ammonia], mitochondrial
Molecular Weight
164938.145 Da
References
  1. Authors unspecified: Carglumic acid: a second look. Confirmed progress in a rare urea cycle disorder. Prescrire Int. 2008 Apr;17(94):50-1. [PubMed:18516804]
  2. Hart EJ, Powers-Lee SG: Role of Cys-1327 and Cys-1337 in redox sensitivity and allosteric monitoring in human carbamoyl phosphate synthetase. J Biol Chem. 2009 Feb 27;284(9):5977-85. doi: 10.1074/jbc.M808702200. Epub 2008 Dec 23. [PubMed:19106093]
  3. Kasapkara CS, Ezgu FS, Okur I, Tumer L, Biberoglu G, Hasanoglu A: N-carbamylglutamate treatment for acute neonatal hyperammonemia in isovaleric acidemia. Eur J Pediatr. 2011 Jun;170(6):799-801. doi: 10.1007/s00431-010-1362-9. Epub 2011 Jan 5. [PubMed:21207059]

Drug created on September 14, 2010 10:21 / Updated on November 12, 2018 07:33