|Bioavailability||39–84% (rodents); ≥ 31% (humans)|
|Biological half-life||2–3 hours|
|Chemical and physical data|
|Molar mass||242.65894 g/mol|
|3D model (Jmol)||Interactive image|
L-4-Chlorokynurenine (4-Cl-KYN; developmental code name AV-101) is an orally active small molecule prodrug candidate that in vivo produces a glycine binding site NMDA receptor antagonist. AV-101 is in clinical development by VistaGen Therapeutics. Inc. as a potential new generation, fast-acting antidepressant, and for other central nervous system (CNS) indications. The initial Phase 2 clinical study of AV-101 is expected to begin in 2015 and will be focused on treatment-resistant depression (TRD) and major depressive disorder (MDD).
Therapeutic indications and mechanism of action
AV-101, or its active metabolite 7-chlorokynurenic acid (7-Cl-KYNA), shows neuroprotective effects in animal models of excitotoxic neurotoxicity anticonvulsant effects in animal models of epilepsy, and depression, and has been found to activate dopaminergic neurons.
Currently-approved antidepressants, including commonly-prescribed selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), have limited effectiveness. Approximately one-third of patients with MDD are not effectively treated by the currently-approved antidepressants, and because of their mechanism of action (MOA), SSRIs and SNRIs must be taken for several weeks before patients experience any significant therapeutic benefit. AV-101’s MOA is fundamentally different from the MOA of SSRIs, SNRIs and all other approved medications for treating depression, placing it together with Ketamine, Rapastinel (GLYX-13) and other new generation of safe, fast-acting, glutamatergic antidepressants under development. This new generation of antidepressants target the N-methyl-D-aspartate receptor (NMDA receptor or NMDAR), or the glycine co-agonist site of the NMDAR, and have the potential to treat the millions of depression sufferers who are poorly served by SSRIs, SNRIs and other existing medications.
In vivo, AV-101 is converted into active 7-Cl-KYNA, one of the most potent and selective NMDAR glycine binding site antagonists, and therefore, unlike classic NMDA receptor antagonists, such as ketamine, phencyclidine (PCP), lanicemine, and dizocilpine (MK-801), instead of blocking the ion channel, AV-101 down-regulates the NMDAR activity. AV-101 is an orally-available prodrug, which is in contrast to ketamine, and other new generation NMDA receptor modulators, such as the peptide rapastinel (GLYX-13), that are given via intravenous injection. AV-101 is efficiently and rapidly transported across the blood–brain barrier (BBB) by neutral amino acid transporter, and is converted in the brain into 7-Cl-KYNA. Although 7-Cl-KYNA, is well known as one of the most potent and selective antagonists of the glycine regulatory site of the NMDAR, and its neuroprotective and antidepressant activities have been well documented, 7-Cl-KYNA does not cross the BBB and therefore is not suitable as a drug for CNS indications.
The Central Nervous System (CNS) conversion of AV-101 into active 7-Cl-KYNA, takes place primarily in astrocytes, and is catalyzed by kynurenine aminotransferases, KAT I and KAT II. Once produced, 7-Cl-KYNA is released into the synapse where it is able to help regulate post-synaptic neurons as well as GABAergic interneurons. The KAT enzymes are involved in the kynurenine pathway associated with the metabolism of the amino acid tryptophan and the production of kynurenic acid (KYNA). KYNA is a natural neuroactive compound with known anti-excitotoxic and anticonvulsant properties, which help regulate dopaminergic pathways. The biology of the kynurenines, and the regulation of the conversion of AV-101 into active 7-Cl-KYNA have significant therapeutic importance. The expression of the KAT enzymes is significantly upregulated in areas of inflammation, neuronal damage, and other pathological processes, which results in a local increase in the production of 7-Cl-KYNA, which may result in a focal increase of the active drug in the regions of pathology and greatest therapeutic need.
The metabolism of AV-101 has an additional potential therapeutic benefit, due to its potential to down regulate the production of quinolinic acid (QA). In addition to the production of 7-Cl-KYNA, AV-101 is also metabolized to 4-Cl-3-hydroxyanthranilic acid, a potent inhibitor of 3-hydroxyanthranilic acid oxygenase (3HAO) (IC50: ~6 nM), the enzyme responsible for the production of QA synthesis. QA is a potent NMDA receptor agonist, convulsant, and endogenous excitotoxic brain constituent. Abnormal increase in the QA/KYNA ratio in the brain has been associated with seizures and excitotoxic neurodegeneration, as well as neurological pathologies such as Huntington’s disease, seizures, and depression, and schizophrenia.
AV-101 has completed two double-blind, placebo-controlled Phase 1 clinical safety studies funded by the U.S. National Institutes of Health (NIH). Both of these NIH-funded Phase 1 safety studies demonstrated that AV-101 is safe and well-tolerated, even at the highest dose studied, with the frequency and degree of adverse events no different than seen in the placebo control groups.
Under the February 2015 Cooperative Research and Development Agreement (CRADA) between VistaGen and the NIH, an NIH-sponsored, double-blind, placebo-controlled Phase 2 clinical study of AV-101 in patients with treatment-resistant MDD will be initiated at the U.S. National Institute of Mental Health (NIMH) in 2015.
- Apimostinel (NRX-1074)
- Buprenorphine/samidorphan (ALKS-5461)
- Neboglamine (nebostinel)
- Rapastinel (GLYX-13)
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- AV-101 (4-Cl-KYN) - VistaGen Therapeutics
- AV-101 and Major Depressive Disorder - VistaGen Therapeutics