ArticlePloS one2018
Improvement of kynurenine aminotransferase-II inhibitors guided by mimicking sulfate esters.
Article in PloS one, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 14 citations in OpenAlex.
- Identification of Two Flavonoids as New and Safe Inhibitors of Kynurenine Aminotransferase II via Computational and In Vitro Study.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Review
- Tryptophan Metabolism in Central Nervous System Diseases: Pathophysiology and Potential Therapeutic Strategies.Aging and disease · 2023Review
- Heterocyclic Cathinones as Inhibitors of Kynurenine Aminotransferase II-Design, Synthesis, and Evaluation.Pharmaceuticals (Basel, Switzerland) · 2021Article
- A Potential Interface between the Kynurenine Pathway and Autonomic Imbalance in Schizophrenia.International journal of molecular sciences · 2021Review
- RAS inhibition modulates kynurenine levels in a CKD population with and without type 2 diabetes mellitus.International urology and nephrology · 2020Observational
- Kynurenines and the Endocannabinoid System in Schizophrenia: Common Points and Potential Interactions.Molecules (Basel, Switzerland) · 2019Review
- Tryptophan Metabolism: A Versatile Area Providing Multiple Targets for Pharmacological Intervention.Egyptian journal of basic and clinical pharmacology · 2019Article
- The Synthesis of Kynurenic Acid in Mammals: An Updated Kynurenine Aminotransferase Structural KATalogue.Frontiers in molecular biosciences · 2019Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The mammalian kynurenine aminotransferase (KAT) enzymes are a family of related isoforms that are pyridoxal 5'-phosphate-dependent, responsible for the irreversible transamination of kynurenine to kynurenic acid. Kynurenic acid is implicated in human diseases such as schizophrenia where it is found in elevated levels and consequently KAT-II, as the isoform predominantly responsible for kynurenic acid production in the brain, has been targeted for the development of specific inhibitors. One class of compounds that have also shown inhibitory activity towards the KAT enzymes are estrogens and their sulfate esters. Estradiol disulfate in particular is very strongly inhibitory and it appears that the 17-sulfate makes a significant contribution to its potency. The work here demonstrates that the effect of this moiety can be mirrored in existing KAT-II inhibitors, from the development of two novel inhibitors, JN-01 and JN-02. Both inhibitors were based on NS-1502 (IC50: 315 μM), but the deliberate placement of a sulfonamide group significantly improved the potency of JN-01 (IC50: 73.8 μM) and JN-02 (IC50: 112.8 μM) in comparison to the parent compound. This 3-4 fold increase in potency shows the potential of these moieties to be accommodated in the KAT-II active site and the effect they can have on improving inhibitors, and the environments in the KAT-II have been suitably modelled using docking calculations.
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