Table 1.
Effect of Varying the Diamine Fragment on Potency, Cytotoxicity, and in Vitro Biopharmaceutical Properties
| entry/cmpd | structure | cell-based assay activity | in vitro pharmacokinetic assays | ||||
|---|---|---|---|---|---|---|---|
|
potency, EC50 (μM)a | cytotoxicity, CC50 (μM)a | selectivity index (CC50/EC50) | rat liver microsome stability t1/2 (min) | PAMPA permeability (1×10−6 cm/s) | aqueous solubility ((μg/ml) | |
| 7a |
|
0.138 ± 0.134 (n=8) | 13.4 ± 2.258 | 97 | >30.0 | 489.1 | 53.9 |
| 7b |
|
0.050 ± 0.025 | 9.390 ± 0.348 | 188 | 14 | 553.7 | >69.0 |
| 7c |
|
0.181 ± 0.104 | 3.467 ± 0.266 | 19 | 5.5 | 1267 | NDb |
| 7d |
|
0.083 ± 0.046 | 4.377 ± 0.260 | 53 | 5.7 | >1397 | NDb |
| 7e |
|
0.056 ± 0.015 | 4.283 ± 0.135 | 76 | 8.8 | 395.6 | >71.0 |
| 7f |
|
0.066 ± 0.029 | 10.153 ± 0.393 | 154 | >30.0 | 241.4 | >69.0 |
| 7g |
|
0.225 ± 0.160 | 12.267 ± 0.586 | 55 | >30.0 | 424.7 | >67.0 |
| 7h |
|
0.473 ± 0.300 | 18.1 ± 0.800 | 38 | >30.0 | 34.5 | >65.0 |
| 7i |
|
0.120 ± 0.023 | 21.300 ± 1.277 | 178 | >30.0 | 55.4 | >69.0 |
| 7j |
|
0.037 ± 0.006 | 15.000 ± 1.572 | 405 | >30.0 | NDb | >67.0 |
| 7k |
|
0.054 ± 0.013 | 5.823 ± 1.541 | 108 | 19.4 | NDb | >71 |
| 7l |
|
0.094 ± 0.018 | 4.640 ± 0.243 | 49 | 2.3 | 3 | 54.9 |
| 7m |
|
0.106 ± 0.034 | 10.867 ± 0.252 | 103 | 7.4 | 330.9 | >71 |
| 7n |
|
0.156 ± 0.035 | 24.437 ± 4.502 | 157 | >30.0 | 712.4 | >67.0 |
| 7o |
|
0.113 ± 0.065 | 23.133 ± 4.155 | 205 | 12 | 287.8 | >71.0 |
| 7p |
|
0.341 ± 0.142 | 30.467 ± 4.225 | 89 | >30.0 | 913.1 | >65.0 |
| 7q |
|
1.063 ± 0.727 | 65.300 ± 3.387 | 61 | >30.0 | 432.4 | >65.0 |
| 7r |
|
1.621 ± 1.426 | 19.933 ± 2.159 | 12 | >30.0 | <3.2 | >71.0 |
| 7s |
|
2.789 ± 2.800 | 27.233 ± 2.060 | 10 | >30.0 | 14 | >67.0 |
a
Average of three separate assays (unless otherwise noted) ± standard deviation.
b
ND, not determined.