Novel Selective IDO1 Inhibitors with Isoxazolo[5,4-]pyrimidin-4(5)-one Scaffold.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising target in immunomodulation of several pathological conditions, especially cancers. Here we present the synthesis of a series of IDO1 inhibitors with the novel isoxazolo[5,4-]pyrimidin-4(5)-one scaffold. A focused library was prepared using a 6- or 7-step synthetic procedure to allow a systematic investigation of the structure-activity relationships of the described scaffold. Chemistry-driven modifications lead us to the discovery of our best-in-class inhibitors possessing -trifluoromethyl (), -cyclohexyl (), or -methoxycarbonyl (, ) substituted aniline moieties with IC values in the low micromolar range. In addition to hIDO1, compounds were tested for their inhibition of indoleamine 2,3-dioxygenase 2 and tryptophan dioxygenase, and found to be selective for hIDO1. Our results thus demonstrate a successful study on IDO1-selective isoxazolo[5,4-]pyrimidin-4(5)-one inhibitors, defining promising chemical probes with a novel scaffold for further development of potent small-molecule immunomodulators.