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

详细信息    查看全文

• 作者：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 Wu ; Shiow-Lin Pan ; Ming-Shiu Hung ; Shau-Hua Ueng
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：January 14, 2016
• 年：2016
• 卷：59
• 期：1
• 页码：419-430
• 全文大小：498K
• ISSN：1520-4804

文摘

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.