Table 2.
Effect of Varying the Aryl Substitution on Potency, Cytotoxicity, and in Vitro Biopharmaceutical Properties
| entry/ cmpd |
structure | cell-based activity and cytotoxicity | 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) |
solubility (μg/ml) |
||
| 7t |
|
|
0.096 ± 0.027 | 16.483 ± 3.963 | 172 | >30.0 | 279.1 | >69.0 |
| 7u |
|
|
0.070 ± 0.038 | 4.333 ± 2.012 | 62 | >30.0 | 274.3 | >69.0 |
| 7v |
|
|
0.111 ± 0.035 | 9.323 ± 0.784 | 84 | 17 | 106.1 | 55.9 |
| 7w |
|
|
0.091 ± 0.037 | 21.033 ± 4.910 | 231 | 3.1 | 253.9 | 55.9 |
| 7x |
|
|
0.093 ± 0.022 | 6.910 ± 0.834 | 74 | >30.0 | 219.4 | >71.0 |
| 7y |
|
|
0.076 ± 0.016 | 4.113 ± 0.122 | 54 | >30.0 | 353.1 | >71.0 |
| 7z |
|
|
0.037 ± 0.031 | 4.05 ± 0.108 | 109 | <30.0 | 864 | >71.0 |
| 7aa |
|
|
0.098 ± 0.29 | 4.070 ± 0.130 | 42 | 30 | NDb | 56.1 |
| 7bb |
|
|
0.190 ± 0.094 | 6.573 ± 1.253 | 35 | >30 | NDb | NDb |
| 7cc |
|
|
0.149 ± 0.074 | 8.183 ± 0.671 | 55 | NDb | 455.2 | NDb |
| 7dd |
|
|
0.057 ± 0.025 | 16.500 ± 1.735 | 289 | 15 | 352.4 | >72.0 |
| 7ee |
|
|
0.094 ± 0.028 | 4.210 ± 0.201 | 45 | >30.0 | 615.1 | >72.0 |
| 7ff |
|
|
0.041 ± 0.025 | 11.517 ± 6.370 | 281 | >30.0 | >635.0 | >72.0 |
| 7gg |
|
|
0.053 ± 0.029 | 12.800 ± 2.307 | 242 | 28.1 | ND | NDb |
| 7hh |
|
|
0.196 ± 0.024 | 13.233 ± 0.252 | 68 | 2.9 | NDb | >77.0 |
| 7ii |
|
|
0.013 ± 0.008 | 3.17 ± 0.635 | 244 | >30 | 522 | NDb |
| 7jj |
|
|
0.421 ± 0.229 | 32.667 ± 1.159 | 78 | 21 | 82.4 | >72.0 |
| 7kk |
|
|
0.539 ± 0.343 | 12.633 ± 2.307 | 23 | 3.9 | 129.9 | NDb |
| 7ll |
|
|
0.220 ± 0.144 | 6.497 ± 0.166 | 30 | 2.1 | <1.0 | 62.4 |
| 7mm |
|
|
0.193 ± 0.086 | 12.200 ± 0.173 | 63 | 1.4 | NDb | >83.0 |
| 7nn |
|
|
0.124 ± 0.087 (n=6) | 12.750 ± 1.569 | 103 | 2.9 | 196.3 | >74.0 |
| 7oo |
|
|
0.370 ± 0.179 (n=2) | 16.411 ± 0.501 | 44 | 5.4 | 650.6 | 52.6 |
| 7pp |
|
|
0.220 ± 0.060 | 11.700 ± 0.361 | 53 | 4.4 | NDb | >74 |
| 7qq |
|
|
0.124 ± 0.059 | 4.907 ± 0.364 | 40 | 2 | NDb | >76 |
| 7rr |
|
|
0.326 ± 0.083 | 12.033 ± 0.723 | 37 | 1.8 | NDb | 65.1 |
| 7ss |
|
|
0.226 ± 0.088 | 13.000 ± 0.458 | 58 | 4.4 | 233.8 | >72.0 |
| 7tt |
|
|
0.351 ± 0.167 | 14.900 ± 0.520 | 42 | 3.5 | 245.3 | >83.0 |
| 7uu |
|
|
0.243 ± 0.195 | 15.833 ± 0.513 | 65 | 3.3 | 51.0 | >76.0 |
| 7vv |
|
|
0.577 ± 0.238 | 37.000 ± 2.946 | 64 | 8.6 | NDb | >74.0 |
| 7ww |
|
|
0.428 ± 0.057 | 16.700 ± 0.265 | 39 | 4.6 | 197.7 | >73.0 |
| 7xx |
|
|
3.110 ± 0.199 | 77.133 ± 12.596 | 25 | 12 | NDb | >76.0 |
| 7yy |
|
|
0.440 ± 0.264 | 57.233 ± 3.213 | 130 | >30.0 | 81.9 | >76.0 |
| 7zz |
|
|
33.983 ± 24.162 | >100 | >3 | >30.0 | 10.4 | >72.0 |
| 7aaa |
|
|
0.052 ± 0.021 | 4.307 ± 0.479 | 83 | >30.0 | NDb | >74.0 |
| 7bbb |
|
|
0.097 ± 0.024 | 4.057 ± 0.177 | 42 | 4.9 | 547.1 | >76.0 |
| 7ccc |
|
|
0.357 ± 0.147 | 4.277 ± 0.110 | 12 | 22 | NDb | 62.1 |
a
Average of three separate assays (unless otherwise noted) ± standard deviation.
b
ND, not determined.