Yuta Ishizuka    Department   Kawasaki Medical School  Kawasaki Medical School, Department of Pathophysiology and Metabolism,    Position   Assistant Professor
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