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Synfacts 2017; 13(08): 0781
DOI: 10.1055/s-0036-1590682
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Epacadostat

Contributor(s):
Philip Kocienski
Coombs AP. * et al. Incyte Corporation, Wilmington, USA
INCB24360 (Epacadostat), a Highly Potent and Selective Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitor for Immuno-oncology.

ACS Med. Chem. Lett. 2017;
8: 486-491
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Further Information

Publication History

Publication Date:
18 July 2017 (online)

 
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Key words

epacadostat - indoleamine-2,3-dioxygenase 1 inhibitors - furazan ring formation - Boulton–Katritzky rearrangement - hydroxyamidines

Significance

Epacadostat (INCB24360) inhibits the immunomodulatory activity of indoleamine-2,3-dioxygenase 1, thereby making possible the restoration and/or activation of the immune system in cancer therapy. In combination with pembrolizumab, epacadostat is currently in a phase III clinical trial for the treatment of metastatic melanoma.


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Comment

Synthesis of the secondary 3-amino-furazan G by direct alkylation or reductive amination of the primary 3-amino substituent in E was low yielding, presumably due to the electron deficiency of the furazan. A general and robust alternate route to secondary amino-furazan G was ­accomplished through a Boulton–Katritzky rearrangement of the amidooxime furazan E.


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