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),1461-1474頁
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