イシヅカ　ユウタ   Yuta Ishizuka   石塚　佑太    所属   川崎医科大学  医学部 基礎医学　病態代謝学    職種   講師
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Discovery and biological characterization of a novel scaffold for potent inhibitors of peripheral serotonin synthesis.
掲載誌名	正式名：Future medicinal chemistry 略　 称：Future Med Chem ISSNコード：17568927/17568919
掲載区分	国外
出版社	Future Science
巻・号・頁	12(16),pp.1461-1474
著者・共著者	Nibal Betari,* Kristoffe Sahlholmr, Yuta Ishizuka, Knut Teigen, Jan Haavik
発行年月	2020/08
概要	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