Novel Selective IDO1 Inhibitors with Isoxazolo[5,4-<i>d</i>]pyrimidin-4(5<i>H</i>)-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-<i>d</i>]pyrimidin-4(5<i>H</i>)-one scaffold. A foc...
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| Main Authors: | , , , , , , |
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| Format: | Book |
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MDPI AG,
2021-03-01T00:00:00Z.
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| Summary: | 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-<i>d</i>]pyrimidin-4(5<i>H</i>)-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 <i>p</i>-trifluoromethyl (<b>23</b>), <i>p</i>-cyclohexyl (<b>32</b>), or <i>p</i>-methoxycarbonyl (<b>20</b>, <b>39</b>) substituted aniline moieties with IC<sub>50</sub> 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-<i>d</i>]pyrimidin-4(5<i>H</i>)-one inhibitors, defining promising chemical probes with a novel scaffold for further development of potent small-molecule immunomodulators. |
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| Item Description: | 10.3390/ph14030265 1424-8247 |