AV-101

AV-101 (L-4-chlorokynurenine; 4-Cl-KYN) is an orally active small-molecule prodrug of 7-chlorokynurenic acid (7-Cl-KYNA), a potent and selective full antagonist of the glycine co-agonist (GlyB) site of the N-methyl-D-aspartate (NMDA) receptor. The compound exploits a physiological transport and enzymatic conversion strategy: after oral absorption, 4-Cl-KYN crosses the blood-brain barrier via the large neutral amino acid transporter 1 (LAT1/SLC7A5) and is converted within astrocytes by kynurenine aminotransferase II (KAT-II) to 7-Cl-KYNA, which is then released into the neuronal synapse as the pharmacologically active species. This prodrug design circumvents the principal limitation of direct glycine site antagonists, namely their inability to penetrate the blood-brain barrier, while concentrating the active metabolite preferentially in regions of neural injury where astrocytic kynurenine aminotransferase activity is upregulated. The parent compound 7-Cl-KYNA was first characterized by Kemp et al. (1988) at Merck Sharp and Dohme Research Laboratories as a selective glycine site antagonist with an IC50 of 0.56 micromolar at the strychnine-insensitive glycine binding site and approximately 300-fold selectivity over the NMDA recognition site [1].

The prodrug strategy was conceived through collaboration between Robert Schwarcz at the University of Maryland and scientists at Marion Merrell Dow. Hokari et al. (1996) demonstrated that systemically administered 4-Cl-KYN is actively transported across the blood-brain barrier with a Km of 105 micromolar and converted to 7-Cl-KYNA in vivo [2]. The compound was advanced through Artemis Neuroscience (founded to develop Schwarcz's kynurenine pathway research) and subsequently acquired by VistaGen Therapeutics in 2003, which assigned the developmental code AV-101 and advanced the compound through two Phase 1 clinical trials in 86 healthy volunteers, a Phase 2 randomized crossover trial in treatment-resistant major depressive disorder at the National Institute of Mental Health, a Phase 1 crossover biomarker trial in healthy military veterans, and preclinical programs in neuropathic pain, levodopa-induced dyskinesia in Parkinson's disease, epilepsy, and Huntington's disease. The United States Food and Drug Administration granted Fast Track designation for AV-101 as a potential adjunctive treatment for major depressive disorder and as a non-opioid treatment for neuropathic pain.

Pharmacokinetics in humans demonstrate oral bioavailability of at least 31 percent, a plasma half-life of approximately 1.7 hours for the parent compound and 2.3 to 3.2 hours for the active metabolite, dose-linear Cmax values across the 30 to 1800 mg single-dose range, and predominantly renal excretion (76 percent). A critical pharmacokinetic limitation was identified: cerebrospinal fluid concentrations of 7-Cl-KYNA were frequently below detection limits at clinically tested doses, suggesting insufficient central nervous system conversion. Preclinical studies have demonstrated that co-administration with probenecid (an inhibitor of the organic anion transporters OAT1/3 and MRP4 responsible for brain efflux of 7-Cl-KYNA) produces up to an 885-fold increase in prefrontal cortex 7-Cl-KYNA concentration, a finding that has informed ongoing clinical development of the AV-101 plus probenecid combination.

The Phase 2 randomized, double-blind, placebo-controlled crossover trial at the National Institute of Mental Health in 19 patients with treatment-resistant depression found no antidepressant effect for 4-Cl-KYN monotherapy at doses of 1080 to 1440 mg daily over 14 days [7]. This negative result, together with the low cerebrospinal fluid 7-Cl-KYNA concentrations, has redirected development toward higher-exposure strategies (probenecid combination) and toward the levodopa-induced dyskinesia indication, where preclinical data in MPTP-lesioned marmosets demonstrated a 25 percent reduction in dyskinesia scores with maintained antiparkinsonian efficacy [9]. The compound has been well tolerated across all completed clinical studies, with no psychotomimetic effects, no drug-related serious adverse events, and an adverse-event profile qualitatively and quantitatively similar to placebo.