Design, synthesis and biological evaluation of novel naphthoquinone derivatives as IDO1 inhibitors.

Authors :: Pan L
Zheng Q
Chen Y
Yang R
Yang Y
Li Z
Meng X
Source :: European journal of medicinal chemistry [Eur J Med Chem] 2018 Sep 05; Vol. 157, pp. 423-436. Date of Electronic Publication: 2018 Aug 07.
Publication Year :: 2018
Abstract: Indoleamine 2,3-dioxygenase 1 (IDO1) mediated kynurenine pathway of tryptophan degradation is identified as an appealing and novel target in immunotherapy for the treatment of cancer. In this study, a novel series of naphthoquinone derivatives were synthesized, characterized and evaluated for their inhibitory activities against IDO1, and their structure-activity relationship was investigated. Among them, compounds T16, T44, T47, T49, T53 and T54 displayed potent IDO1 inhibitory activities with IC <subscript>50</subscript> values ranging between 18 and 61 nM, which are more potent than INCB024360 undergoing clinical trial III evaluation. In addition, compounds T28, T44 and T53 decreased the kynurenine levels in rat plasma by 30%-50%. Compounds exhibiting excellent IDO1 inhibitory activities were also evaluated for their inhibitory activities against tryptophan 2,3-dioxygenase (TDO). Of which, compound T28 (IDO1 IC <subscript>50</subscript>  = 120 nM) showed promising TDO inhibition (IC <subscript>50</subscript> 72 nM) and was identified as an IDO1/TDO dual inhibitor.<br /> (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

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