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Identification
- Summary
L-Acetylleucine is a modified form of leucine used to treat neurological symptoms in patients with Niemann-Pick disease type C.
- Brand Names
- Aqneursa
- Generic Name
- L-Acetylleucine
- DrugBank Accession Number
- DB16956
- Background
Levacetylleucine (L-acetylleucine) is a modified acetylated derivative of the amino acid leucine. The racemic (i.e. DL-) form has been available in France since 1957 for the treatment of vertigo.2
Observational studies in patients with Niemann-Pick disease type C (NPC) suggested a beneficial symptomatic as well as neuroprotective disease-modifying effect of the DL-form of N-acetylleucine, after which animal studies showed that the L-enantiomer (i.e. levacetylleucine) has potential clinical benefits compared to the racemic mixture.2 In September 2024, the FDA approved levacetylleucine for the treatment of select patients with NPC.4
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for L-Acetylleucine (DB16956)
- Weight
- Average: 173.212
Monoisotopic: 173.105193347 - Chemical Formula
- C8H15NO3
- Synonyms
- (s)-2-acetamido-4-methylpentanoic acid
- Acetyl-l-leucine
- Acetylleucine, (s)-
- Acetylleucine, l-
- L-leucine, n-acetyl-
- Leucine, n-acetyl-, l-
- N-acetyl leucine
- N-acetyl-l-(-)-leucine
- N-acetyl-l-leucine
- N-Acetyl-Leucine
- N-acetylleucine
- External IDs
- NSC-206316
Pharmacology
- Indication
Levacetylleucine is indicated for the treatment of neurological symptoms of Niemann-Pick disease type C (NPC) in adults and pediatric patients weighing ≥15 kg.3
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Symptomatic treatment of Niemann-pick disease, type c •••••••••••• •••••• ••••••••• •••• •••••• •• •• ••••• •• •• •••••••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
The pharmacodynamics of levacetylleucine are not well characterized. There does not appear to be a relationship between increasing levacetylleucine exposure and clinical efficacy.3
- Mechanism of action
Following oral administration, levacetylleucine is taken up via ubiquitously expressed monocarboxylate transporters and distributed to all body tissues.1 It enters enzyme-controlled pathways that correct metabolic dysfunction and improves adenosine triphosphate (ATP) energy production.1 The normalization of energy metabolism ameliorates mitochondrial and lysosomal dysfunction and leads to a reduction in the storage of unesterified cholesterol and sphingolipids.1 Levacetylleucine has also been shown to normalize neuronal membrane potentials in a guinea pig model, thereby improving cellular signaling processes and restoring and protecting neuronal circuits.1
The specific molecular target of levacetylleucine in the context of Niemann-Pick disease type C (NPC) is unknown.3
- Absorption
The Cmaxand AUC0-24h of levacetylleucine following oral administration were 8.3 μg/mL and 33.2 h*μg/mL, respectively.3 The time to maximum concentration (Tmax) is approximately 1 hour.3
- Volume of distribution
The apparent volume of distribution following oral administration of levacetylleucine is 253 liters.3
- Protein binding
Not Available
- Metabolism
Levacetylleucine is metabolized into acetate and L-leucine by ubiquitously expressed enzymes.3
Hover over products below to view reaction partners
- Route of elimination
Not Available
- Half-life
The half-life of levacetylleucine is approximately 1 hour.3
- Clearance
The apparent oral clearance of levacetylleucine is 139 L/h.3
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
There are no data available regarding overdosage with levacetylleucine.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbemaciclib The serum concentration of Abemaciclib can be increased when it is combined with L-Acetylleucine. Afatinib The serum concentration of Afatinib can be increased when it is combined with L-Acetylleucine. Ambrisentan The serum concentration of Ambrisentan can be increased when it is combined with L-Acetylleucine. Apixaban The serum concentration of Apixaban can be increased when it is combined with L-Acetylleucine. Avanafil The serum concentration of Avanafil can be increased when it is combined with L-Acetylleucine. - Food Interactions
- Take with or without food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Aqneursa Granule, for suspension 1000 mg/1 Oral IntraBio Inc 2024-09-24 Not applicable US 
Brand name Granule, for solution 1000 mg/1 Oral IntraBio Inc 2024-01-18 Not applicable US - Unapproved/Other Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Brand name L-Acetylleucine (1000 mg/1) Granule, for solution Oral IntraBio Inc 2024-01-18 Not applicable US
Categories
- Drug Categories
- Classification
- Not classified
- Affected organisms
- Humans
Chemical Identifiers
- UNII
- E915HL7K2O
- CAS number
- 1188-21-2
- InChI Key
- WXNXCEHXYPACJF-ZETCQYMHSA-N
- InChI
- InChI=1S/C8H15NO3/c1-5(2)4-7(8(11)12)9-6(3)10/h5,7H,4H2,1-3H3,(H,9,10)(H,11,12)/t7-/m0/s1
- IUPAC Name
- (2S)-2-acetamido-4-methylpentanoic acid
- SMILES
- CC(C)C[C@H](NC(C)=O)C(O)=O
References
- Synthesis Reference
H. D. DeWitt and A. W. Ingersoll. The Preparation of Pure N-Acetyl-L-leucine and L-Leucine. Journal of the American Chemical Society 1951 73 (7), 3359-3360. DOI: 10.1021/ja01151a108
- General References
- Bremova-Ertl T, Ramaswami U, Brands M, Foltan T, Gautschi M, Gissen P, Gowing F, Hahn A, Jones S, Kay R, Kolnikova M, Arash-Kaps L, Marquardt T, Mengel E, Park JH, Reichmannova S, Schneider SA, Sivananthan S, Walterfang M, Wibawa P, Strupp M, Martakis K: Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C. N Engl J Med. 2024 Feb 1;390(5):421-431. doi: 10.1056/NEJMoa2310151. [Article]
- Fields T, M Bremova T, Billington I, Churchill GC, Evans W, Fields C, Galione A, Kay R, Mathieson T, Martakis K, Patterson M, Platt F, Factor M, Strupp M: N-acetyl-L-leucine for Niemann-Pick type C: a multinational double-blind randomized placebo-controlled crossover study. Trials. 2023 May 29;24(1):361. doi: 10.1186/s13063-023-07399-6. [Article]
- FDA Approved Drug Products: Aqneursa (levacetylleucine) for oral suspension (September 2024) [Link]
- FDA News Release: FDA Approves New Drug to Treat Niemann-Pick Disease, Type C [Link]
- External Links
- Human Metabolome Database
- HMDB0011756
- KEGG Compound
- C02710
- ChemSpider
- 64075
- 2375522
- ChEBI
- 17786
- ChEMBL
- CHEMBL56021
- ZINC
- ZINC000000135384
- PDBe Ligand
- LAY
- PDB Entries
- 5afg / 5nfu
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Completed Not Available Alcohol Dependency 1 somestatus stop reason just information to hide Not Available Completed Not Available Ankylosing Spondylitis (AS) / Carotid Artery Plaque / Rheumatoid Arthritis 1 somestatus stop reason just information to hide Not Available Completed Not Available Healthy Volunteers (HV) 1 somestatus stop reason just information to hide Not Available Completed Not Available High Grade Glioma: Glioblastoma (GBM) 1 somestatus stop reason just information to hide Not Available Completed Not Available Hypertriglyceridemias / Resistance, Insulin 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Granule, for suspension Oral 1000 mg/1 Granule, for solution Oral 1000 mg/1 - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 10.9 mg/mL ALOGPS logP 0.78 ALOGPS logP 0.49 Chemaxon logS -1.2 ALOGPS pKa (Strongest Acidic) 4.2 Chemaxon pKa (Strongest Basic) -1.8 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 66.4 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 43.61 m3·mol-1 Chemaxon Polarizability 18.07 Å3 Chemaxon Number of Rings 0 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- General Function
- Secondary active transporter that functions as a Na(+)-independent organic anion (OA)/dicarboxylate antiporter where the uptake of one molecule of OA into the cell is coupled with an efflux of one molecule of intracellular dicarboxylate such as 2-oxoglutarate or glutarate (PubMed:11669456, PubMed:11907186, PubMed:14675047, PubMed:22108572, PubMed:23832370, PubMed:28534121, PubMed:9950961). Mediates the uptake of OA across the basolateral side of proximal tubule epithelial cells, thereby contributing to the renal elimination of endogenous OA from the systemic circulation into the urine (PubMed:9887087). Functions as a biopterin transporters involved in the uptake and the secretion of coenzymes tetrahydrobiopterin (BH4), dihydrobiopterin (BH2) and sepiapterin to urine, thereby determining baseline levels of blood biopterins (PubMed:28534121). Transports prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may contribute to their renal excretion (PubMed:11907186). Also mediates the uptake of cyclic nucleotides such as cAMP and cGMP (PubMed:26377792). Involved in the transport of neuroactive tryptophan metabolites kynurenate (KYNA) and xanthurenate (XA) and may contribute to their secretion from the brain (PubMed:22108572, PubMed:23832370). May transport glutamate (PubMed:26377792). Also involved in the disposition of uremic toxins and potentially toxic xenobiotics by the renal organic anion secretory pathway, helping reduce their undesired toxicological effects on the body (PubMed:11669456, PubMed:14675047). Uremic toxins include the indoxyl sulfate (IS), hippurate/N-benzoylglycine (HA), indole acetate (IA), 3-carboxy-4- methyl-5-propyl-2-furanpropionate (CMPF) and urate (PubMed:14675047, PubMed:26377792). Xenobiotics include the mycotoxin ochratoxin (OTA) (PubMed:11669456). May also contribute to the transport of organic compounds in testes across the blood-testis-barrier (PubMed:35307651)
- Specific Function
- alpha-ketoglutarate transmembrane transporter activity
- Gene Name
- SLC22A6
- Uniprot ID
- Q4U2R8
- Uniprot Name
- Solute carrier family 22 member 6
- Molecular Weight
- 61815.78 Da
References
- FDA Approved Drug Products: Aqneursa (levacetylleucine) for oral suspension (September 2024) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- General Function
- Functions as an organic anion/dicarboxylate exchanger that couples organic anion uptake indirectly to the sodium gradient (PubMed:14586168, PubMed:15644426, PubMed:15846473, PubMed:16455804, PubMed:31553721). Transports organic anions such as estrone 3-sulfate (E1S) and urate in exchange for dicarboxylates such as glutarate or ketoglutarate (2-oxoglutarate) (PubMed:14586168, PubMed:15846473, PubMed:15864504, PubMed:22108572, PubMed:23832370). Plays an important role in the excretion of endogenous and exogenous organic anions, especially from the kidney and the brain (PubMed:11306713, PubMed:14586168, PubMed:15846473). E1S transport is pH- and chloride-dependent and may also involve E1S/cGMP exchange (PubMed:26377792). Responsible for the transport of prostaglandin E2 (PGE2) and prostaglandin F2(alpha) (PGF2(alpha)) in the basolateral side of the renal tubule (PubMed:11907186). Involved in the transport of neuroactive tryptophan metabolites kynurenate and xanthurenate (PubMed:22108572, PubMed:23832370). Functions as a biopterin transporters involved in the uptake and the secretion of coenzymes tetrahydrobiopterin (BH4), dihydrobiopterin (BH2) and sepiapterin to urine, thereby determining baseline levels of blood biopterins (PubMed:28534121). May be involved in the basolateral transport of steviol, a metabolite of the popular sugar substitute stevioside (PubMed:15644426). May participate in the detoxification/ renal excretion of drugs and xenobiotics, such as the histamine H(2)-receptor antagonists fexofenadine and cimetidine, the antibiotic benzylpenicillin (PCG), the anionic herbicide 2,4-dichloro-phenoxyacetate (2,4-D), the diagnostic agent p-aminohippurate (PAH), the antiviral acyclovir (ACV), and the mycotoxin ochratoxin (OTA), by transporting these exogenous organic anions across the cell membrane in exchange for dicarboxylates such as 2-oxoglutarate (PubMed:11669456, PubMed:15846473, PubMed:16455804). Contributes to the renal uptake of potent uremic toxins (indoxyl sulfate (IS), indole acetate (IA), hippurate/N-benzoylglycine (HA) and 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF)), pravastatin, PCG, E1S and dehydroepiandrosterone sulfate (DHEAS), and is partly involved in the renal uptake of temocaprilat (an angiotensin-converting enzyme (ACE) inhibitor) (PubMed:14675047). May contribute to the release of cortisol in the adrenals (PubMed:15864504). Involved in one of the detoxification systems on the choroid plexus (CP), removes substrates such as E1S or taurocholate (TC), PCG, 2,4-D and PAH, from the cerebrospinal fluid (CSF) to the blood for eventual excretion in urine and bile (By similarity). Also contributes to the uptake of several other organic compounds such as the prostanoids prostaglandin E(2) and prostaglandin F(2-alpha), L-carnitine, and the therapeutic drugs allopurinol, 6-mercaptopurine (6-MP) and 5-fluorouracil (5-FU) (By similarity). Mediates the transport of PAH, PCG, and the statins pravastatin and pitavastatin, from the cerebrum into the blood circulation across the blood-brain barrier (BBB). In summary, plays a role in the efflux of drugs and xenobiotics, helping reduce their undesired toxicological effects on the body (By similarity)
- Specific Function
- organic anion transmembrane transporter activity
- Gene Name
- SLC22A8
- Uniprot ID
- Q8TCC7
- Uniprot Name
- Organic anion transporter 3
- Molecular Weight
- 59855.585 Da
References
- FDA Approved Drug Products: Aqneursa (levacetylleucine) for oral suspension (September 2024) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
References
- FDA Approved Drug Products: Aqneursa (levacetylleucine) for oral suspension (September 2024) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- Broad substrate specificity ATP-binding cassette transporter ABCG2
- Molecular Weight
- 72313.47 Da
References
- FDA Approved Drug Products: Aqneursa (levacetylleucine) for oral suspension (September 2024) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Catalyzes the transport of the major hydrophobic bile salts, such as taurine and glycine-conjugated cholic acid across the canalicular membrane of hepatocytes in an ATP-dependent manner, therefore participates in hepatic bile acid homeostasis and consequently to lipid homeostasis through regulation of biliary lipid secretion in a bile salts dependent manner (PubMed:15791618, PubMed:16332456, PubMed:18985798, PubMed:19228692, PubMed:20010382, PubMed:20398791, PubMed:22262466, PubMed:24711118, PubMed:29507376, PubMed:32203132). Transports taurine-conjugated bile salts more rapidly than glycine-conjugated bile salts (PubMed:16332456). Also transports non-bile acid compounds, such as pravastatin and fexofenadine in an ATP-dependent manner and may be involved in their biliary excretion (PubMed:15901796, PubMed:18245269)
- Specific Function
- ABC-type bile acid transporter activity
- Gene Name
- ABCB11
- Uniprot ID
- O95342
- Uniprot Name
- Bile salt export pump
- Molecular Weight
- 146405.83 Da
References
- FDA Approved Drug Products: Aqneursa (levacetylleucine) for oral suspension (September 2024) [Link]
Drug created at September 14, 2022 22:04 / Updated at October 20, 2024 05:39