Table 1. Summary of Hydrolytic and Enzymatic Stability Profiles and IKZF1 Degradation Data of Phthalimide-Based CRBN Ligands Substituted at Positions 4 or 5a.
| compound | logD7.4 | % stability pH 7.4b | % IKZF1 depletionc | plasma t1/2 (min)d |
|---|---|---|---|---|
| T01 | 3.1 | 80 | 64 | >120 |
| T02 | 2.6 | 70 | 19 | n.d. |
| T03 | 2.6 | 15 | 14 | 118 |
| T04 | 2.3 | 11 | 1 | n.d. |
| T05 | 2.6 | 46 | 5 | n.d. |
| T06 | 2.9 | 30 | 0 | >120 |
| T07 | 2.1 | 68 | 29 | >120 |
| T08 | 1.8 | 56 | 6 | n.d. |
| T09 | 2.0 | 17 | 0 | n.d. |
| T10 | 2.0 | 15 | 0 | n.d. |
| T11 | 2.0 | 21 | 73 | >120 |
| T12 | 1.8 | 16 | 0 | n.d. |
| T13 | 3.2 | 6 | n.d. | n.d. |
| T14 | 3.3 | 1 | n.d. | n.d. |
| T15 | 1.9 | 3 | n.d. | n.d. |
| T16 | 1.9 | 1 | n.d. | n.d. |
| L01 | 2.4 | 74 | 5 | >120 |
| L02 | 2.1 | 79 | 0 | n.d. |
| L03 | 1.6 | 79 | 0 | 87 |
| L04 | 1.8 | 73 | 6 | n.d. |
| L05 | 2.3 | 78 | 22 | n.d. |
| L06 | 2.2 | 73 | 16 | >120 |
| CC2 | n.d. | 19 | n.d. | n.d. |
| CC3 | n.d. | 90 | n.d. | n.d. |
| CC4 | n.d. | 99 | n.d. | n.d. |
a
n.d. = not determined.
b
Percentage stability refers to the remaining starting material as determined by HPLC after incubation for 24 h in pH 7.4 buffer. Values represent the mean of three independent repeats.
c
Percentage IKZF1 degradation in MM.1S cells treated with a 1 μM concentration of the compounds for 6 h. Values are normalized to DMSO-treated cells and the loading controls (100%) and represent the mean of six independent repeats.
d
In vitro plasma stability as determined by HPLC after incubation in human plasma.