Table 4.
In Vitro Pharmacological Activity of Class I Derivatives (Compounds 27a–e and 34a–h)a
| Class I | Binding (Ki)/Transactivation (IC50) (μM) | SARD Activity (% degradation) | |||
|---|---|---|---|---|---|
|
|
|
|
|||
| (ID) | Ki (DHT=1nM)b | IC50b | Full Lengthb (LNCaP) @1 μM | Splice Variantb (22RV1) @10 μM | |
| 8 | 0.267 | 0.085 | 76 | 87 | |
| 27a | 0.091 | 1.079 | 19, 87e | 87 | |
| 27b | 0.729 | 0.871 | 48 | 60 | |
| 27c | 0.194 | 0.991 | 20 | 29 | |
| 27d | 0.249 | 1.243 | 38 | 0g | |
| 27e | 0.810 | 1.025 | 51 | -f | |
| 34a | 3.615 | 0.277 | 70 | 0g | |
| Class I | 34b | >100 | 0.687 | 60 | 0g |
| 34c | 1.476 | 0.560 | 40 | 0g | |
| 34d | >100 | >100 | -f | -f | |
| 34e | >100 | N/Af | -f | -f | |
| 34f | >100 | -g | -f | -f | |
| 34g | >100 | 2.594 | -f | -f | |
| 34h | >100 | >100 | -f | -f | |
| 1 [R-Bicalutamide] | 0.509 | 0.248 | 0g | 0g | |
| 2 [Enzalutamide] | 3.641 | 0.216 | 0g | 0g | |
| 4 [Darolutamide] | 4.231 | 0.048 | -f | -f | |
| 6 [Enobosarm]c | 0.0038 | 0.0038c | Agonistd | Agonistd | |
a
Class I and II derivatives were in which the B-ring was substituted quinoline, carbazole, or benzotriazole were found to be selective androgen receptor degraders (SARDs).
b
AR binding, transactivation, and degradation assays were performed.
c
In vitro transcriptional activation was run in agonist mode for which the EC50 value was previously reported.13
d
The full agonist Enobosarm (compound 6) increases AR protein expression.
e
In vitro transcriptional activation was run in antagonist mode for which the IC50 value was previously reported.13 Tested at 10 μM concentration.
f
Not available (N/A).
g
No effect.