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Structure-based design of xanthine-benzimidazole derivatives as novel and potent tryptophan hydroxylase inhibitors

Item Type:Article
Title:Structure-based design of xanthine-benzimidazole derivatives as novel and potent tryptophan hydroxylase inhibitors
Creators Name:Specker, E. and Matthes, S. and Wesolowski, R. and Schütz, A. and Grohmann, M. and Alenina, N. and Pleimes, D. and Mallow, K. and Neuenschwander, M. and Gogolin, A. and Weise, M. and Pfeifer, J. and Ziebart, N. and Heinemann, U. and von Kries, J.P. and Nazaré, M. and Bader, M.
Abstract:Tryptophan hydroxylases catalyze the first and rate-limiting step in the synthesis of serotonin. Serotonin is a key neurotransmitter in the central nervous system and, in the periphery, functions as a local hormone with multiple physiological functions. Studies in genetically altered mouse models have shown that dysregulation of peripheral serotonin levels leads to metabolic, inflammatory, and fibrotic diseases. Overproduction of serotonin by tumor cells causes severe symptoms typical for the carcinoid syndrome, and tryptophan hydroxylase inhibitors are already in clinical use for patients suffering from this disease. Here, we describe a novel class of potent tryptophan hydroxylase inhibitors, characterized by spanning all active binding sites important for catalysis, specifically those of the cosubstrate pterin, the substrate tryptophan as well as directly chelating the catalytic iron ion. The inhibitors were designed to efficiently reduce serotonin in the periphery while not passing the blood-brain barrier, thus preserving serotonin levels in the brain.
Keywords:Benzimidazoles, Serotonin, Tryptophan, Tryptophan Hydroxylase, Xanthine, Animals, Mice
Source:Journal of Medicinal Chemistry
Publisher:American Chemical Society
Page Range:11126-11149
Date:25 August 2022
Official Publication:https://doi.org/10.1021/acs.jmedchem.2c00598
PubMed:View item in PubMed

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