Phenyl Benzenesulfonylhydrazides Exhibit Selective Indoleamine 2,3-Dioxygenase Inhibition with Potent in Vivo Pharmacodynamic Activity and Antitumor Efficacy
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2016 |
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| Erschienen: |
2016 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:59 |
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| Enthalten in: |
Journal of medicinal chemistry - 59(2016), 1 vom: 14. Jan., Seite 419-30 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lin, Shu-Yu [VerfasserIn] |
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| Links: |
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| Themen: |
343-65-7 |
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| Anmerkungen: |
Date Completed 18.05.2016 Date Revised 14.01.2016 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.5b01640 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM255430388 |
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| 245 | 1 | 0 | |a Phenyl Benzenesulfonylhydrazides Exhibit Selective Indoleamine 2,3-Dioxygenase Inhibition with Potent in Vivo Pharmacodynamic Activity and Antitumor Efficacy |
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| 500 | |a Date Revised 14.01.2016 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Song, Jen-Shin |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Ming-Fu |e verfasserin |4 aut | |
| 700 | 1 | |a Liao, Fang-Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Chao, Min-Wu |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Han-Li |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yi-Lin |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Chun-Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Mine-Hsine |e verfasserin |4 aut | |
| 700 | 1 | |a Hsieh, Chia-Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Hsiao, Wenchi |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Yi-Hui |e verfasserin |4 aut | |
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| 700 | 1 | |a Sun, Manwu |e verfasserin |4 aut | |
| 700 | 1 | |a Chao, Yu-Sheng |e verfasserin |4 aut | |
| 700 | 1 | |a Shih, Chuan |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Su-Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Pan, Shiow-Lin |e verfasserin |4 aut | |
| 700 | 1 | |a Hung, Ming-Shiu |e verfasserin |4 aut | |
| 700 | 1 | |a Ueng, Shau-Hua |e verfasserin |4 aut | |
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