Abstract
Kynurenic acid is a neuroprotective metabolite of tryptophan formed by kynurenine aminotransferase (KAT) catalyzed transformation of kynurenine. However, its high brain levels are associated with cognitive deficit and with the pathophysiology of schizophrenia. Although several classes of KAT inhibitors have been published, the search for new inhibitor chemotypes is crucial for the process of finding suitable clinical candidates. Therefore, we used pharmacophore modeling and molecular docking, which predicted derivatives of heterocyclic amino ketones as new potential irreversible inhibitors of kynurenine aminotransferase II. Thiazole and triazole-based amino ketones were synthesized within a SAR study and their inhibitory activities were evaluated in vitro. The observed activities confirmed our computational model and, moreover, the best compounds showed sub-micromolar inhibitory activity with 2-alaninoyl-5-(4-fluorophenyl)thiazole having IC50 = 0.097 µM.
Highlights
Kynurenic acid (KYNA) is a neuroactive metabolite produced in L-tryptophan catabolism, in the kynurenine pathway (Figure 1)
KYNA is formed via irreversible transamination from L-kynurenine and the reaction is catalyzed by a class of enzymes called kynurenine aminotransferases (KATs) [12]
KAT-I–IV, KAT-II is predominant in brain tissue and plays the primary role of KYNA
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. KAT-I–IV, KAT-II is predominant in brain tissue and plays the primary role of KYNA biosynthesis in neurons [13,14]. Studies on mice have proven that the inhibition of KAT-II leads to improvement. Pharmaceuticals 2021, 14, 1291 role of KYNA biosynthesis in neurons [13,14]. KAT-II is a good target for lowering brain levels of KYNA. Studies on mice have proven that the inhibition of KAT-II leads to improvement cognitive functions, highlighting the potential of KAT-II inin cognitive functions, in highlighting the potential use of KAT-II inhibitorsuse in schizophrenia hibitors in schizophrenia treatment [4,11,15].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
