Steeneck C.
*
Kinzel O,
Anderhub S,
Hornberger M,
Pinto S,
Morschhaeuser B,
Braun F,
Kleymann G,
Hoffmann T.
Phenex Pharmaceuticals AG, Heidelberg, Germany
Discovery of Hydroxyamidine Based Inhibitors of IDO1 for Cancer Immunotherapy with Reduced Potential for Glucuronidation.
ACS Med. Chem. Lett. 2020;
11: 179-187
Key words
indoleamine-2,3-dioxygenase-1 inhibitor - 1,2,4-oxadiazole - S
NAr reaction
Significance
Indoleamine-2,3-dioxygenase-1 (IDO1) is strongly involved in tumor immune resistance. The immune suppressive effect of IDO1 results from its capacity to degrade tryptophan to N-formylkyurenine, the first and rate-limiting step of the kyurenine pathway. The target molecule N is a low-nanomolar IDO1 inhibitor.
Comment
Reaction of aldoxime F with N-chlorosuccinimide (NCS) afforded N-hydroxycarbimidoyl chloride G. Treatment of G with 3-chloroaniline followed by hydroxyamidine cyclization using 1,1′-carbonyldiimidazole (CDI) and Boc deprotection afforded the key amino intermediate K.
