Phenyl Benzenesulfonylhydrazides Exhibit Selective Indoleamine 2,3-Dioxygenase Inhibition with Potent in Vivo Pharmacodynamic Activity and Antitumor Efficacy

Shu Yu Lin, Teng Kuang Yeh, Ching Chuan Kuo, Jen Shin Song, Ming Fu Cheng, Fang Yu Liao, Min Wu Chao, Han Li Huang, Yi Lin Chen, Chun Yu Yang, Mine Hsine Wu, Chia Ling Hsieh, Wenchi Hsiao, Yi Hui Peng, Jian Sung Wu, Li Mei Lin, Manwu Sun, Yu Sheng Chao, Chuan Shih, Su Ying WuShiow Lin Pan, Ming Shiu Hung, Shau Hua Ueng

研究成果: 雜誌貢獻文章同行評審

55 引文 斯高帕斯(Scopus)

摘要

Tryptophan metabolism has been recognized as an important mechanism in immune tolerance. Indoleamine 2,3-dioxygenase plays a key role in local tryptophan metabolism via the kynurenine pathway and has emerged as a therapeutic target for cancer immunotherapy. Our prior study identified phenyl benzenesulfonyl hydrazide 2 as a potent in vitro (though not in vivo) inhibitor of indoleamine 2,3-dioxygenase. Further lead optimization to improve in vitro potencies and pharmacokinetic profiles resulted in N′-(4-bromophenyl)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl hydrazide 40, which demonstrated 59% oral bioavailability and 73% of tumor growth delay without apparent body weight loss in the murine CT26 syngeneic model, after oral administration of 400 mg/kg. Accordingly, 40, is proposed as a potential drug lead worthy of advanced preclinical evaluation.
原文英語
頁(從 - 到)419-430
頁數12
期刊Journal of Medicinal Chemistry
59
發行號1
DOIs
出版狀態已發佈 - 一月 14 2016

ASJC Scopus subject areas

  • 分子醫學
  • 藥物發現

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