CARGLUMIC ACID

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C6H10N2O5
Molecular Weight	190.154
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC(=O)N[C@@H](CCC(O)=O)C(O)=O

InChI

InChIKey=LCQLHJZYVOQKHU-VKHMYHEASA-N

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

HIDE SMILES / InChI

Molecular Formula	C6H10N2O5
Molecular Weight	190.154
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022562lbl.pdf | http://www.recordati.com/resources/Pubblicazione/___e5f362471c2c448d873585839d6dd521_/carbaglu-authorized-in-canada.pdf

Carglumic acid is a Carbamoyl Phosphate Synthetase 1 (CPS 1) allosteric modulator. 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. Carglumic acid under the trade name Carbaglu indicated as adjunctive therapy for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). In addition, as maintenance therapy for the treatment of chronic hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). 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.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Carbamoyl-phosphate synthase [ammonia], mitochondrial 2 Target ID: CHEMBL2362990 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21403788	Positive Allosteric Modulator 178

Conditions

Condition	Modality	Targets	Highest Phase	Product
Acute hyperammonemia 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022562lbl.pdf	Primary		Approved 8307	CARBAGLU Approved Use Carbaglu (carglumic acid) is a Carbamoyl Phosphate Synthetase 1 (CPS 1) activator indicated as: • Adjunctive therapy for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). (1.1) • Maintenance therapy for the treatment of chronic hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). (1.2) Launch Date 1.26887041E12
Chronic hyperammonemia 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022562lbl.pdf	Palliative		Approved 8307	CARBAGLU Approved Use Carbaglu (carglumic acid) is a Carbamoyl Phosphate Synthetase 1 (CPS 1) activator indicated as: • Adjunctive therapy for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). (1.1) • Maintenance therapy for the treatment of chronic hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). (1.2) Launch Date 1.26887041E12

C_max

Value	Dose	Co-administered	Analyte	Population
2892 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25677217/	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		CARGLUMIC ACID plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
2.6 μg/mL REVIEW https://pubmed.ncbi.nlm.nih.gov/30780843/	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		CARGLUMIC ACID plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
23.2 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25677217/	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		CARGLUMIC ACID plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
5.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25677217/	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		CARGLUMIC ACID plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
5.6 h REVIEW https://pubmed.ncbi.nlm.nih.gov/30780843/	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		CARGLUMIC ACID plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
96.3 mg/kg 2 times / day multiple, oral Recommended Dose: 96.3 mg/kg, 2 times / day Route: oral Route: multiple Dose: 96.3 mg/kg, 2 times / day Sources: https://ojrd.biomedcentral.com/articles/10.1186/s13023-016-0406-2	unhealthy, 5 day n = 21 Health Status: unhealthy Condition: methylmalonic aciduria Age Group: 5 day Sex: M+F Population Size: 21 Sources: https://ojrd.biomedcentral.com/articles/10.1186/s13023-016-0406-2	Sources: https://ojrd.biomedcentral.com/articles/10.1186/s13023-016-0406-2

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1670	inhibitor 1695	inhibitor 1789

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1463 CYP2B6 770 CYP2A6 670 CYP2C8 869 CYP2C19 1410 CYP2E1 846 CYP3A4/5 261	CYP1A 22 CYP2B 10 CYP1A2 1013	CYP1A 55 CYP2B6 521 CYP3A4/5 112

Drug as perpetrator

Target	Modality	Activity
CYP1A 119	inducer 1515 Sources: https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_A100_2.pdf#page=23, https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_I100_1.pdf#page=38 Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 11-12, 38	no
CYP1A2 1620	inhibitor 3185 Sources: https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_A100_2.pdf#page=23, https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_I100_1.pdf#page=12 Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42	no
CYP2A6 702	inhibitor 3185 Sources: https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_A100_2.pdf#page=23, https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_I100_1.pdf#page=12 Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42	no
CYP2B6 946	inducer 1515 Sources: https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_A100_2.pdf#page=23, https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_I100_1.pdf#page=38 Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 11-12, 38	no
CYP2B6 946	inhibitor 3185 Sources: https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_A100_2.pdf#page=23, https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_I100_1.pdf#page=12 Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42	no
CYP2C19 1484	inhibitor 3185 Sources: https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_A100_2.pdf#page=23, https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_I100_1.pdf#page=12 Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42	no
CYP2C8 923	inhibitor 3185 Sources: https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_A100_2.pdf#page=23, https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_I100_1.pdf#page=12 Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42	no
CYP2C9 1747	inhibitor 3185 Sources: https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_A100_2.pdf#page=23, https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_I100_1.pdf#page=12 Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42	no
CYP2D6 1826	inhibitor 3185 Sources: https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_A100_2.pdf#page=23, https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_I100_1.pdf#page=12 Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42	no
CYP2E1 929	inhibitor 3185 Sources: https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_A100_2.pdf#page=23, https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_I100_1.pdf#page=12 Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42	no
CYP3A4/5 314	inducer 1515 Sources: https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_A100_2.pdf#page=23, https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_I100_1.pdf#page=38 Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 11-12, 38	no
CYP3A4/5 314	inhibitor 3185 Sources: https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_A100_2.pdf#page=23, https://www.pmda.go.jp/drugs/2016/P20161021006/710794000_22800AMX00708_I100_1.pdf#page=12 Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42	no

Drug as victim

Target	Modality	Activity
CYP1A 22	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022562s000pharmr.pdf#page=30 Page: 30, 35	no
CYP1A2 1013	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022562s000pharmr.pdf#page=30 Page: 30.0	no
CYP2B 10	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022562s000pharmr.pdf#page=30 Page: 30.0	no
CYP3A4 1670	substrate 3264 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022562s000pharmr.pdf#page=30 Page: 30.0	no

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:71028	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:71028
ChemicalBook	CB6183743	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB6183743
MolPort	MolPort-012-207-739	https://www.molport.com/shop/molecule-link/MolPort-012-207-739
ZINC	ZINC000001530283	http://zinc15.docking.org/substances/ZINC000001530283
eMolecules	8294431	https://www.emolecules.com/cgi-bin/more?vid=8294431

PubMed

Title	Date	PubMed
[Orphan drugs and metabolic disorders].	2001 Aug 1-15	11588713
Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients.	2001 Sep	11518822
N-acetylglutamate synthase deficiency and the treatment of hyperammonemic encephalopathy.	2002 Dec	12447942
N-carbamylglutamate enhances ammonia detoxification in a patient with decompensated methylmalonic aciduria.	2003 Aug	12948747
Hyperammonaemia as a cause of psychosis in an adolescent.	2003 Nov	12942317
Mammalian N-acetylglutamate synthase.	2004 Apr	15050968
Carglumic acid: new preparation. An advance in rare urea cycle disorders.	2004 Feb	15055204
Urea synthesis by ruminal epithelial and duodenal mucosal cells from growing sheep.	2004 Jun	15453495
Restoration of ureagenesis in N-acetylglutamate synthase deficiency by N-carbamylglutamate.	2004 Oct	15480384
N-carbamylglutamate protects patients with decompensated propionic aciduria from hyperammonaemia.	2005	15877213
Neonatal hyperammonemia: the N-carbamoyl-L-glutamic acid test.	2005 Aug	16126063
Misleading diagnosis of partial N-acetylglutamate synthase deficiency based on enzyme measurement corrected by mutation analysis.	2005 Jan	15858972
Metabolic fates of ammonia-N in ruminal epithelial and duodenal mucosal cells isolated from growing sheep.	2005 Nov	16230702
Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene.	2007 Aug	17421020
A trial with N-carbamylglutamate may not detect all patients with NAGS deficiency and neonatal onset.	2007 Jun	17510757
Carglumic acid: a second look. Confirmed progress in a rare urea cycle disorder.	2008 Apr	18516804
N-carbamylglutamate markedly enhances ureagenesis in N-acetylglutamate deficiency and propionic acidemia as measured by isotopic incorporation and blood biomarkers.	2008 Aug	18414145
N-carbamylglutamate for neonatal hyperammonaemia in propionic acidaemia.	2008 Dec	18338235
Carglumic acid: an additional therapy in the treatment of organic acidurias with hyperammonemia?	2008 Jan 30	18234091
[A newborn infant with hyperventilation].	2008 Jun 26	18604903
Uncovering metabolic pathways relevant to phenotypic traits of microbial genomes.	2009	19284550
[N-carbamyl glutamate treatment in hyperammoniemia decompensated propionic acidaemia].	2009 Dec	19850540
Effects of a single dose of N-carbamylglutamate on the rate of ureagenesis.	2009 Dec	19660971
Pricing of orphan drugs.	2009 Feb 7	19200917
The first use of N-carbamylglutamate in a patient with decompensated maple syrup urine disease.	2009 Sep	19688253
N-acetylglutamate synthase: structure, function and defects.	2010	20303810
N-carbamylglutamate in emergency management of hyperammonemia in neonatal acute onset propionic and methylmalonic aciduria.	2010	19887858
Outpatient treatment of propionic acidemia-associated hyperammonemia with N-carbamoyl-L-glutamate in an infant.	2010 Apr	20435240
Dietary supplementation with L-arginine or N-carbamylglutamate enhances intestinal growth and heat shock protein-70 expression in weanling pigs fed a corn- and soybean meal-based diet.	2010 Aug	20213438
Gateways to clinical trials.	2010 Dec	21225012
Favourable long-term outcome after immediate treatment of neonatal hyperammonemia due to N-acetylglutamate synthase deficiency.	2010 Feb	19533169
Biochemical efficacy of N-carbamylglutamate in neonatal severe hyperammonaemia due to propionic acidaemia.	2010 Jan	19680687
N-carbamylglutamate augments ureagenesis and reduces ammonia and glutamine in propionic acidemia.	2010 Jul	20566609
Carglumic acid approved to treat genetic hyperammonemia.	2010 May 1	20410539
Role of carglumic acid in the treatment of acute hyperammonemia due to N-acetylglutamate synthase deficiency.	2011	21941437

Patents

Sample Use Guides

In Vivo Use Guide

Adult Dosage: The recommended initial dose for acute hyperammonemia is 100 mg/kg/day to 250 mg/kg/day. Concomitant administration of other ammonia lowering therapies is recommended. Dosing should be titrated based on individual patient plasma ammonia levels and clinical symptoms. The recommended maintenance dose should be titrated to target normal plasma ammonia level for age. Based on limited data in 22 patients receiving maintenance treatment with Carbaglu in a retrospective case series, maintenance doses were usually less than 100 mg/kg/day. The total daily dose should be divided into 2 to 4 doses and rounded to the nearest 100 mg. (i.e. half a Carbaglu Tablet) Pediatric Dosage: The recommended initial dose for acute hyperammonemia is 100 mg/kg/day to 250 mg/kg/day. Concomitant administration of other ammonia lowering therapies is recommended. Dosing should be titrated based on individual patient plasma ammonia levels and clinical symptoms. The recommended maintenance dose should be titrated to target normal plasma ammonia level for age. Based on limited data in 22 patients receiving maintenance treatment with Carbaglu in a retrospective case series, maintenance doses were usually less than 100 mg/kg/day. The total daily dose should be divided into 2 to 4 doses.

Route of Administration: Oral

In Vitro Use Guide

Carglumic acid-treated (1, 5, 10 mM) and untreated cancer cells were stained with propidium iodide to determine DNA contents in the human pancreatic adenocarcinoma cell lines, AsPC1 and human triple-negative breast cancer cell lines MDA-MB-231. The results showed that carglumic acid did not induce complete cell cycle arrest. Instead, we observed more sub-G1 cells among carglumic acid-treated AsPC1 and MDA-MB-231 cells than among untreated cells, indicating that cell death occurred in response to carglumic acid. Sub-G1 cells accounted for 1.6% and 26.3% of untreated and treated AsPC1 cells, respectively , and for 1.8% and 12.8% of untreated and treated MDA-MB-231 cells, respectively. In order to further determine whether cancer cells under go cell death through apoptosis after carglumic acid treatment, we measured caspase activity in AsPC1 cells treated with carglumic acid. The results showed that caspase-3 activity increased in a dose-dependent manner. Together, these data suggest that carglumic acid inhibits cancer cell proliferation by inducing apoptosis.

Substance Class	Chemical Created by `admin` on `Fri Dec 16 20:32:46 UTC 2022` Edited by `admin` on `Fri Dec 16 20:32:46 UTC 2022`
Record UNII	5L0HB4V1EW
Record Status	`Validated (UNII)`
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Name

Type

Language

CARGLUMIC ACID

Official Name

English

CARBAMYL-L-GLUTAMIC ACID

Systematic Name

English

N-CARBAMYL-L-GLUTAMIC ACID

Common Name

English

L-GLUTAMIC ACID, N-(AMINOCARBONYL)-

Common Name

English

CARGLUMIC ACID [JAN]

Common Name

English

CARGLUMIC ACID [EMA EPAR]

Common Name

English

CARGLUMIC ACID [USP-RS]

Common Name

English

CARGLUMIC ACID [ORANGE BOOK]

Common Name

English

CARGLUMIC ACID [MART.]

Common Name

English

Carglumic acid [WHO-DD]

Common Name

English

OE-312

Code

English

NSC-760124

Code

English

OE 312

Code

English

CARGLUMIC ACID [MI]

Common Name

English

carglumic acid [INN]

Common Name

English

N-CARBAMYLGLUTAMATE

Systematic Name

English

CARGLUMIC ACID [VANDF]

Common Name

English

CARGLUMIC ACID [USAN]

Common Name

English

CARBAGLU

Brand Name

English

N-CARBAMOYL-L-GLUTAMIC ACID

Systematic Name

English

Classification Tree Code System Code

EMA ASSESSMENT REPORTS

CARBAGLU (AUTHORIZED: AMINO ACID METABOLISM, INBORN ERRORS)