Table 1.
Structure-activity relationship of NTRC 3883-0 and analogues.
 | ||||||||
|---|---|---|---|---|---|---|---|---|
| Compound | Configuration | R1 | R2 | R3 | R4 | R5 | IC50 IDO1 (nM) | IC50 A375 (nM) |
| 1 | R/S | 3-Br-Ph | – | – | – | – | 1,220 | 4,520 |
| 2a | R/S | Ph | – | – | – | – | > 31,600 | > 31,600 |
| 2b | R/S | 3-Cl-Ph | – | – | – | – | 2,380 | 5,220 |
| 2c | R/S | 2-Br-Ph | – | – | – | – | > 31,600 | > 31,600 |
| 2d | R/S | 4-Br-Ph | – | – | – | – | > 31,600 | > 31,600 |
| 2e | R/S | cyclohexyl | – | – | – | – | > 31,600 | > 31,600 |
| 2f | R/S | 3-CN-Ph | – | – | – | – | 17,900 | > 31,600 |
| 2g | R/S | 3-CF3-Ph | – | – | – | – | 2,460 | 5,290 |
| 3a | R/S | – | H | H | H | F | 2,170 | 11,000 |
| 3b | R/S | – | H | H | F | H | 910 | 5,240 |
| 3c | R/S | – | F | H | H | H | 479 | 1,150 |
| 3d | R/S | – | CH3 | H | H | H | 4,020 | 21,700 |
| 3e | R/S | – | OCH3 | H | H | H | > 31,600 | > 31,600 |
| 3f | R/S | – | Cl | H | H | H | 784 | 4600 |
| 3g | R/S | – | Br | H | H | H | 1,780 | 12,500 |
| 3h | R/S | – | F | H | F | H | 600 | 2,830 |
| 3i | R/S | – | F | H | H | F | 582 | 2,140 |
| 3j (NTRC 3748-0) | R/S | – | F | F | H | H | 198 | 589 |
| 3k | R | – | F | F | H | H | 2,170 | 4,590 |
| NTRC 3883-0 | S | – | F | F | H | H | 123 | 182 |
NTRC 3883-0 and its analogues were developed by medicinal chemistry optimization from a 3-hydroxyimidazolin-4-one hit compound (1) identified by ultra-high throughput screening. Inhibitory potencies (IC50) were determined in a human IDO1 biochemical assay and a cell-based assay with IFNγ-stimulated A375 human melanoma cells. All analogues were inactive in a biochemical assay for TDO (IC50 > 31.6 µM).