Table 6.
Biological activity and selected ADME data for ring-opened analogs.
| ID | R1 | R2 | T.b.b. pEC50 | MRC5 pTC50 | LLE | Aq. sol. (μM) | cLogP |
|---|---|---|---|---|---|---|---|
| 31c | −H | −NH2 | 5.5 | <4.3 | 4.4 | <13 | 0.87 |
| 51 | −OMe | −NH2 | 6.2 | <4.3 | 5.2 | 196 | 0.71 |
| 57a | −OEt | −NH2 | 6.4 | 5.0 | 5.3 | 861 | 1.1 |
| 57b* | −OiPr | −NH2 | 6.4 | 5.0 | 4.9 | 354 | 1.5 |
| 57c | −OtBu | −NH2 | 6.2 | 4.6 | 4.4 | 68 | 1.8 |
| 57d | −OcyBu | −NH2 | 6.6 | 5.0 | 5.0 | nd | 1.6 |
| 57e* | −OPh | −NH2 | 5.7 | 5.7 | 3.3 | 117 | 2.4 |
| 57f* | −OBn | −NH2 | 5.9 | 5.0 | 3.4 | 85 | 2.4 |
| 57g |  |
−NH2 | 5.5 | <4.3 | 4.9 | 751 | 0.62 |
| 57h |  |
−NH2 | 5.8 | <4.3 | 5.1 | 770 | 0.68 |
| 57i |  |
−NH2 | 6.1 | <4.3 | 5.0 | 1000 | 1.13 |
| 57j |  |
−NH2 | 5.7 | <4.3 | 5.1 | 383 | 0.56 |
| 63 | −H | −NHPh | 5.4 | <4.3 | 2.1 | 3 | 3.1 |
| 68 | −H | −NHBn | 6.1 | <4.3 | 2.2 | 17 | 2.9 |
*
Compound and data provided by GSK; HepG2 toxicity and kinetic aqueous solubility.
All SD within ± 0.16.