Overview on experimental physicochemical properties, CRBN binding data, and neosubstrate degradation for the series of aminoglutarimides 1–6.
| Cmpd | log D7.4a | CHIIAMb | %HSA bindingc | IC50d (μM) | K i d (μM) | % IKZF3e deg |
|---|---|---|---|---|---|---|
| 1 | n.d.f | n.d. | n.d. | 481 ± 340 | 247 ± 177 | 20 |
| 2 | –1.7 | –1.1 | 4.0 | 107 ± 85 | 52 ± 44 | 4 |
| 3g | –0.4 | 4.4 | 12 | 18.9 ± 1.5 | 6.40 ± 0.8 | 84 |
| 4 | 2.2 | 28.5 | 89 | 7.9 ± 1.7 | 0.7 ± 0.9 | 60 |
| 5 | 1.6 | 22.5 | 86 | 8.6 ± 1.1 | 1.1 ± 0.6 | 93 |
| 6 | 2.0 | 25.3 | 90 | 10.5 ± 1.6 | 2.0 ± 0.8 | 57 |
a
Distribution coefficients at pH 7.4 were estimated by an HPLC-based method.
b
Chromatographic hydrophobicity index values referring to IAM chromatography (CHIIAM values), an estimate for drug-membrane interactions and permeability.28
c
Protein binding values were estimated by an HPLC-based method.
d
Affinity values determined in a competitive MST assay as described in the Method sections (see ESI).
e
Percentage of degraded IKZF3 after 24 h treatment of 106 OPM-2 cells per mL with 10 μM of each compound.
f
Not determined.
g
CRBN binding data taken from ref. 29.