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

Research output: Contribution to journalArticlepeer-review

45 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)419-430
Number of pages12
JournalJournal of Medicinal Chemistry
Volume59
Issue number1
DOIs
Publication statusPublished - Jan 14 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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