Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 1, Pages 419-430Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01640
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Funding
- Ministry of Health and Welfare [MOHW103-TDU-212-114006]
- National Health Research Institutes [04A1-BPPP03-005, BP-103-PP-05]
- National Science Council of the Republic of China [100CA007]
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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.
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