Routes of
administration Oral Biological half-life 2–3 hours | ATC code None Molar mass 242.6589 g/mol | |
 | ||
Pregnancy
category US: N (Not classified yet) Legal status US: Investigational New Drug Bioavailability 39–84% (rodents); ≥ 31% (humans) | ||
-4-Chlorokynurenine (4-Cl-KYN; developmental code name AV-101) is an orally active small molecule prodrug of 7-chlorokynurenic acid, a NMDA receptor antagonist. It appears to be a rapid-acting antidepressant.
Contents
AV-101 was discovered at Marion Merrell Dow and its biological activity was explored at University of Maryland. It underwent initial development at Artemis Neuroscience which was acquired by VistaGen in 2003. As of 2016 it was in a Phase II clinical trial for major depressive disorder.
Chemistry
4-Chlorokynurenine is prodrug of 7-chlorokynurenic acid (7-Cl-KYNA), which in turn is a halogenated derivative of L-kynurenine.
Pharmacology
4-Chlorokynurenine penetrates the blood-brain barrier via LAT1 transporters. In the CNS it is converted to 7-chlorokynurenic acid by kynurenine aminotransferase in astrocytes.
Most of its therapeutic potential is believed to occur via 7-chlorokynurenic acid which inhibits the glycine co-agonist site of NMDA receptors.
Another metabolite, 4-chloro-3-hydroxy-anthranilic acid, inhibits the enzyme 3-HAO, which provides a rationale for further testing in neurodegenerative diseases.
History
Artemis Neuroscience was formed to develop work done by University of Maryland professor Robert Schwartz in collaboration with scientists at Marion Merrell Dow (which became part of Sanofi by way of Aventis); this work included AV-101.
VistaGen acquired AV-101 when it acquired Artemis in 2003.
VistaGen filed an Investigational New Drug application with the FDA for use of AV-101 in neuropathic pain in 2013.
As of 2013, other NMDA receptor antagonists in clinical trials for depression included lanicemine, S-ketamine, and GLYX-13, with lancemine being the most advanced.
Research
AV-101 showed efficacy in animal model of Huntington's disease and showed rapid-acting antidepressant effects similar to ketamine in the forced-swim test and two other behavioral models of depression in rodents.
By 2013 AV-101 had successfully gone through two Phase I clinical trials.
As of 2016 a Phase II clinical trial was underway in major depressive disorder.