Yuta Ishizuka
Department Kawasaki Medical School Kawasaki Medical School, Department of Pathophysiology and Metabolism, Position Assistant Professor |
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Article types | 原著 |
Language | English |
Peer review | Peer reviewed |
Title | Discovery and biological characterization of a novel scaffold for potent inhibitors of peripheral serotonin synthesis. |
Journal | Formal name:Future medicinal chemistry Abbreviation:Future Med Chem ISSN code:17568927/17568919 |
Domestic / Foregin | Foregin |
Publisher | Future Science |
Volume, Issue, Page | 12(16),pp.1461-1474 |
Author and coauthor | Nibal Betari,* Kristoffe Sahlholmr, Yuta Ishizuka, Knut Teigen, Jan Haavik |
Publication date | 2020/08 |
Summary | Aim: Tryptophan hydroxylase 1 (TPH1) catalyzes serotonin synthesis in peripheral tissues. Selective TPH1 inhibitors may be useful for treating disorders related to serotonin dysregulation. Results & methodology: Screening using a thermal shift assay for TPH1 binders yielded Compound 1 (2-(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one), which showed high potency (50% inhibition at 98 ± 30 nM) and selectivity for inhibiting TPH over related aromatic amino acid hydroxylases in enzyme activity assays. Structure-activity relationships studies revealed several analogs of 1 showing comparable potency. Kinetic studies suggested a noncompetitive mode of action of 1, with regards to tryptophan and tetrahydrobiopterin. Computational docking studies and live cell assays were also performed. Conclusion: This TPH1 inhibitor scaffold may be useful for developing new therapeutics for treating elevated peripheral serotonin. |
DOI | 10.4155/fmc-2020-0127 |
PMID | 32752885 |