Luvadaxistat

Last updated
Luvadaxistat
Luvadaxistat.svg
Clinical data
Other namesNBI-1065844; NBI1065844; TAK-831; TAK831
Legal status
Legal status
  • Investigational
Identifiers
  • 6-[2-[4-(Trifluoromethyl)phenyl]ethyl]-1,2-dihydropyridazine-3,4-dione
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C13H11F3N2O2
Molar mass 284.238 g·mol−1
3D model (JSmol)
  • C1=CC(=CC=C1CCC2=CC(=O)C(=O)NN2)C(F)(F)F
  • InChI=1S/C13H11F3N2O2/c14-13(15,16)9-4-1-8(2-5-9)3-6-10-7-11(19)12(20)18-17-10/h1-2,4-5,7H,3,6H2,(H,17,19)(H,18,20)
  • Key:QBQMUMMSYHUDFM-UHFFFAOYSA-N

Luvadaxistat (INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name; NBI-1065844, TAK-831) is an experimental drug that works as a D-amino acid oxidase (DAAO) inhibitor and is supposed to increase NMDA receptor functionality. [1] It is developed to treat Friedrich ataxia [2] and negative symptoms of schizophrenia. [3] [4] [5] As of September 2024, it is in phase 2 clinical trials for schizophrenia, no recent development has been reported for ataxia, and the drug has been discontinued for Friedreich's ataxia. [6]

Related Research Articles

<span class="mw-page-title-main">Monoamine oxidase inhibitor</span> Type of medication

Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, especially for treatment-resistant depression and atypical depression. They are also used to treat panic disorder, social anxiety disorder, Parkinson's disease, and several other disorders.

<span class="mw-page-title-main">Phenelzine</span> Antidepressant

Phenelzine, sold under the brand name Nardil among others, is a non-selective and irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine family which is primarily used as an antidepressant and anxiolytic to treat depression and anxiety. Along with tranylcypromine and isocarboxazid, phenelzine is one of the few non-selective and irreversible MAOIs still in widespread clinical use.

Catechol-<i>O</i>-methyltransferase Class of enzymes

Catechol-O-methyltransferase is one of several enzymes that degrade catecholamines, catecholestrogens, and various drugs and substances having a catechol structure. In humans, catechol-O-methyltransferase protein is encoded by the COMT gene. Two isoforms of COMT are produced: the soluble short form (S-COMT) and the membrane bound long form (MB-COMT). As the regulation of catecholamines is impaired in a number of medical conditions, several pharmaceutical drugs target COMT to alter its activity and therefore the availability of catecholamines. COMT was first discovered by the biochemist Julius Axelrod in 1957.

<span class="mw-page-title-main">Friedreich's ataxia</span> Rare autosomal-recessive human disease


Friedreich's ataxia (FRDA) is a rare, inherited, autosomal recessive neurodegenerative disorder that primarily affects the nervous system, causing progressive damage to the spinal cord, peripheral nerves, and cerebellum, leading to impaired muscle coordination (ataxia). The condition typically manifests in childhood or adolescence, with initial symptoms including difficulty walking, loss of balance, and poor coordination. As the disease progresses, it can also impact speech, vision, and hearing. Many individuals with Friedreich's ataxia develop scoliosis, diabetes, and hypertrophic cardiomyopathy, a serious heart condition that is a leading cause of mortality in patients.

<span class="mw-page-title-main">Idebenone</span> Chemical compound

Idebenone, sold under the brand name Raxone among others, is a medication that was initially developed by Takeda Pharmaceutical Company for the treatment of Alzheimer's disease and other cognitive defects. This has been met with limited success. The Swiss company Santhera Pharmaceuticals has started to investigate it for the treatment of neuromuscular diseases. In 2010, early clinical trials for the treatment of Friedreich's ataxia and Duchenne muscular dystrophy have been completed. As of December 2013 the drug is not approved for these indications in North America or Europe. It is approved by the European Medicines Agency (EMA) for use in Leber's hereditary optic neuropathy (LHON) and was designated an orphan drug in 2007.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

<span class="mw-page-title-main">Norepinephrine transporter</span> Protein-coding gene in the species Homo sapiens

The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene.

<span class="mw-page-title-main">Tolcapone</span> Chemical compound

Tolcapone, sold under the brand name Tasmar, is a medication used to treat Parkinson's disease (PD). It is a selective, potent and reversible nitrocatechol-type inhibitor of the enzyme catechol-O-methyltransferase (COMT). It has demonstrated significant liver toxicity, which has led to suspension of marketing authorisations in a number of countries.

<span class="mw-page-title-main">Cycloserine</span> Tuberculosis medication

Cycloserine, sold under the brand name Seromycin, is a GABA transaminase inhibitor and an antibiotic, used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active drug resistant tuberculosis. It is given by mouth.

<span class="mw-page-title-main">D-amino acid oxidase</span> Enzyme

D-amino acid oxidase is an enzyme with the function on a molecular level to oxidize D-amino acids to the corresponding α-keto acids, producing ammonia and hydrogen peroxide. This results in a number of physiological effects in various systems, most notably the brain. The enzyme is most active toward neutral D-amino acids, and not active toward acidic D-amino acids. One of its most important targets in mammals is D-Serine in the central nervous system. By targeting this and other D-amino acids in vertebrates, DAAO is important in detoxification. The role in microorganisms is slightly different, breaking down D-amino acids to generate energy.

<span class="mw-page-title-main">NMDA receptor antagonist</span> Class of anesthetics

NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for humans and animals; the state of anesthesia they induce is referred to as dissociative anesthesia.

Histamine <i>N</i>-methyltransferase Mammalian enzyme involved in the metabolism of histamine

Histamine N-methyltransferase (HNMT) is a protein encoded by the HNMT gene in humans. It belongs to the methyltransferases superfamily of enzymes and plays a role in the inactivation of histamine, a biomolecule that is involved in various physiological processes. Methyltransferases are present in every life form including archaeans, with 230 families of methyltransferases found across species.

Catechol-<i>O</i>-methyltransferase inhibitor Medication

A catechol-O-methyltransferase inhibitor is a drug that inhibits the enzyme catechol-O-methyltransferase. This enzyme methylates catecholamines such as dopamine, norepinephrine and epinephrine. It also methylates levodopa. COMT inhibitors are indicated for the treatment of Parkinson's disease in combination with levodopa and an aromatic L-amino acid decarboxylase inhibitor. The therapeutic benefit of using a COMT inhibitor is based on its ability to prevent the methylation of levodopa to 3-O-methyldopa, thus increasing the bioavailability of levodopa. COMT inhibitors significantly decrease off time in people with Parkinson's disease also taking carbidopa/levodopa.

<span class="mw-page-title-main">Hyperprolinemia</span> Medical condition

Hyperprolinemia is a condition which occurs when the amino acid proline is not broken down properly by the enzymes proline oxidase or pyrroline-5-carboxylate dehydrogenase, causing a buildup of proline in the body.

<span class="mw-page-title-main">Levoamphetamine</span> CNS stimulant and isomer of amphetamine

Levoamphetamine is a stimulant medication which is used in the treatment of certain medical conditions. It was previously marketed by itself under the brand name Cydril, but is now available only in combination with dextroamphetamine in varying ratios under brand names like Adderall and Evekeo. The drug is known to increase wakefulness and concentration in association with decreased appetite and fatigue. Pharmaceuticals that contain levoamphetamine are currently indicated and prescribed for the treatment of attention deficit hyperactivity disorder (ADHD), obesity, and narcolepsy in some countries. Levoamphetamine is taken by mouth.

<span class="mw-page-title-main">Leonurine</span> Chemical compound

Leonurine is a pseudoalkaloid that has been isolated from Leonotis leonurus, Leonotis nepetifolia, Leonurus japonicus, Leonurus cardiaca (motherwort), Leonurus sibiricus, as well as other plants of family Lamiaceae. Leonurine is easily extracted into water.

<span class="mw-page-title-main">GABA reuptake inhibitor</span> Drug class

A GABA reuptake inhibitor (GRI) is a type of drug which acts as a reuptake inhibitor for the neurotransmitter gamma-Aminobutyric acid (GABA) by blocking the action of the gamma-Aminobutyric acid transporters (GATs). This in turn leads to increased extracellular concentrations of GABA and therefore an increase in GABAergic neurotransmission. Gamma-aminobutyric acid (GABA) is an amino acid that functions as the predominant inhibitory neurotransmitter within the central nervous system, playing a crucial role in modulating neuronal activity in both the brain and spinal cord. While GABA predominantly exerts inhibitory actions in the adult brain, it has an excitatory role during developmental stages. When the neuron receives the action potential, GABA is released from the pre-synaptic cell to the synaptic cleft. After the action potential transmission, GABA is detected on the dendritic side, where specific receptors collectively contribute to the inhibitory outcome by facilitating GABA transmitter uptake. Facilitated by specific enzymes, GABA binds to post-synaptic receptors, with GABAergic neurons playing a key role in system regulation. The inhibitory effects of GABA diminish when presynaptic neurons reabsorb it from the synaptic cleft for recycling by GABA transporters (GATs). The reuptake mechanism is crucial for maintaining neurotransmitter levels and synaptic functioning. Gamma-aminobutyric acid Reuptake Inhibitors (GRIs) hinder the functioning of GATs, preventing GABA reabsorption in the pre-synaptic cell. This results in increased GABA levels in the extracellular environment, leading to elevated GABA-mediated synaptic activity in the brain.

<span class="mw-page-title-main">Omaveloxolone</span> Medication

Omaveloxolone, sold under the brand name Skyclarys, is a medication used for the treatment of Friedreich's ataxia. It is taken by mouth.

Deulinoleate ethyl is an experimental, orally-bioavailable synthetic deuterated polyunsaturated fatty acid (PUFA), a part of reinforced lipids. It is an isotopologue of linoleic acid, an essential omega-6 PUFA. The deuterated compound, while identical to natural linoleic acid except for the presence of deuterium, is resistant to lipid peroxidation which makes studies of its cell-protective properties worthwhile.

<span class="mw-page-title-main">Reinforced lipids</span> Deuterated lipid molecules

Reinforced lipids are lipid molecules in which some of the fatty acids contain deuterium. They can be used for the protection of living cells by slowing the chain reaction due to isotope effect on lipid peroxidation. The lipid bilayer of the cell and organelle membranes contain polyunsaturated fatty acids (PUFA) are key components of cell and organelle membranes. Any process that either increases oxidation of PUFAs or hinders their ability to be replaced can lead to serious disease. Correspondingly, use of reinforced lipids that stop the chain reaction of lipid peroxidation has preventive and therapeutic potential.

References

  1. O’Donnell, Patricio; Dong, Cheng; Murthy, Venkatesha; Asgharnejad, Mahnaz; Du, Xiaoming; Summerfelt, Ann; Lu, Hong; Xu, Lin; Wendland, Jens R.; Dunayevich, Eduardo; Buhl, Derek L.; Litman, Robert; Hetrick, William P.; Hong, L. Elliot; Rosen, Laura B. (June 2023). "The D-amino acid oxidase inhibitor luvadaxistat improves mismatch negativity in patients with schizophrenia in a randomized trial". Neuropsychopharmacology. 48 (7): 1052–1059. doi:10.1038/s41386-023-01560-0. ISSN   1740-634X. PMC   10018616 . PMID   36928351.
  2. Wang, Hao; Norton, Jonathan; Xu, Lin; DeMartinis, Nicholas; Sen, Rohini; Shah, Ankit; Farmer, Jennifer; Lynch, David (June 2021). "Results of a randomized double‐blind study evaluating luvadaxistat in adults with Friedreich ataxia". Annals of Clinical and Translational Neurology. 8 (6): 1343–1352. doi:10.1002/acn3.51373. PMC   8164851 . PMID   34018342.
  3. Fradley, Rosa; Goetghebeur, Pascal; Miller, David; Burley, Russell; Almond, Sarah; Gruart i Massó, Agnès; Delgado García, José M.; Zhu, Bin; Howley, Eimear; Neill, Jo C.; Grayson, Ben; Gaskin, Philip; Carlton, Mark; Gray, Ian; Serrats, Jordi; Davies, Ceri H. (October 2023). "Luvadaxistat: A Novel Potent and Selective d-Amino Acid Oxidase Inhibitor Improves Cognitive and Social Deficits in Rodent Models for Schizophrenia". Neurochemical Research. 48 (10): 3027–3041. doi:10.1007/s11064-023-03956-2. PMC   10471729 . PMID   37289348.
  4. Veselinović, Tanja; Neuner, Irene (August 2022). "Progress and Pitfalls in Developing Agents to Treat Neurocognitive Deficits Associated with Schizophrenia". CNS Drugs. 36 (8): 819–858. doi:10.1007/s40263-022-00935-z. PMC   9345797 . PMID   35831706.
  5. Kuo, Chien-Yi; Lin, Chieh-Hsin; Lane, Hsien-Yuan (November 2022). "Targeting d-Amino Acid Oxidase (DAAO) for the Treatment of Schizophrenia: Rationale and Current Status of Research". CNS Drugs. 36 (11): 1143–1153. doi:10.1007/s40263-022-00959-5. PMID   36194364. S2CID   252694226.
  6. "Luvadaxistat". AdisInsight. 18 September 2024. Retrieved 4 November 2024.